AU2003229883A1 - Carbamic acid compounds comprising a piperazine linkage as hdac inhibitors - Google Patents

Carbamic acid compounds comprising a piperazine linkage as hdac inhibitors Download PDF

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AU2003229883A1
AU2003229883A1 AU2003229883A AU2003229883A AU2003229883A1 AU 2003229883 A1 AU2003229883 A1 AU 2003229883A1 AU 2003229883 A AU2003229883 A AU 2003229883A AU 2003229883 A AU2003229883 A AU 2003229883A AU 2003229883 A1 AU2003229883 A1 AU 2003229883A1
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independently
compound according
alkylene
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Klara Dikovska
Paul W. Finn
Vija Gailite
Ivars Kalvinsh
Daina Lolya
Einars Loza
James Ritchie
Maria-Rosario Romero-Martin
Igor Starchenkov
Clare J. Watkins
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Topotarget UK Ltd
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Prolifix Ltd
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/58—Radicals substituted by nitrogen atoms
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

This invention pertains to certain carbamic acid compounds which inhibit HDAC (histone deacetylase) activity of the following formula: The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.

Description

WO 03/082288 PCT/GBO3/01463 -1 CARBAMIC ACID COMPOUNDS COMPRISING A PIPERAZINE LINKAGE AS HDAC INHIBITORS RELATED APPLICATIONS 5 This application is related to (and where permitted by law, claims priority to) U.S. Provisional Application number 60/369,337 filed 03 April 2002, the contents of which are incorporated herein by reference in their entirety. 10 TECHNICAL FIELD This invention pertains generally to the field of biologically active compounds, and more specifically to certain carbamic acid compounds which inhibit HDAC (histone deacetylase) activity. The present invention also pertains to pharmaceutical compositions comprising 15 such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc. BACKGROUND 20 Throughout this specification, including any claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integers 25 or steps. It must be noted that, as used in the specification and any appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of 30 two or more such carriers, and the like. Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values 35 are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.
WO 03/082288 PCT/GB03/01463 -2 DNA in eukaryotic cells is tightly complexed with proteins (histones) to form chromatin. Histones are small, positively charged proteins which are rich in basic amino acids (positively charged at physiological pH), which contact the phosphate groups (negatively 5 charged at physiological pH) of DNA. There are five main classes of histones, H1, H2A, H2B, H3, and H4. The amino acid sequences of histones H2A, H2B, H3, and H4 show remarkable conservation between species, whereas H1 varies somewhat, and in some cases is replaced by another histone, e.g., H5. Four pairs of each of H2A, H2B, H3, and H4 together form a disk-shaped octomeric protein core, around which DNA (about 140 10 base pairs) is wound to form a nucleosome. Individual nucleosomes are connected by short stretches of linker DNA associated with another histone molecule (e.g., H1, or in certain cases, H5) to form a structure resembling a beaded string, which is itself arranged in a helical stack, known as a solenoid. 15 The majority of histones are synthesised during the S phase of the cell cycle, and newly synthesised histones quickly enter the nucleus to become associated with DNA. Within minutes of its synthesis, new DNA becomes associated with histones in nucleosomal structures. 20 A small fraction of histones, more specifically, the amino side chains thereof, are enzymatically modified by post-translational addition of methyl, acetyl, or phosphate groups, neutralising the positive charge of the side chain, or converting it to a negative charge. For example, lysine and arginine groups may be methylated, lysine groups may be acetylated, and serine groups may be phosphorylated. For lysine, the -(CH 2
)
4
-NH
2 25 sidechain may be acetylated, for example by an acetyltransferase enzyme, to give the amide -(CH 2
)
4
-NHC(=O)CH
3 . Methylation, acetylation, and phosphorylation of amino termini of histones which extend from the nucleosomal core affects chromatin structure and gene expression. (See, for example, Spencer and Davie, 1999). 30 Acetylation and deacetylation of histones is associated with transcriptional events leading to cell proliferation and/or differentiation. Regulation of the function of transcription factors is also mediated through acetylation. Recent reviews of histone deacetylation include Kouzarides, 1999 and Pazin et al., 1997. 35 The correlation between the acetylation status of histones and the transcription of genes has been known for over 30 years (see, for example, Howe et al., 1999). Certain WO 03/082288 PCT/GB03/01463 -3 enzymes, specifically acetylases (e.g., histone acetyltransferase, HAT) and deacetylases (e.g., histone deacetylase, HDAC), which regulate the acetylation state of histones have been identified in many organisms and have been implicated in the regulation of numerous genes, confirming the link between acetylation and transcription. See, for 5 example, Davie, 1998. In general, histone acetylation correlates with transcriptional activation, whereas histone deacetylation is associated with gene repression. A growing number of histone deacetylases (HDACs) have been identified (see, for example, Ng and Bird, 2000). The first deacetylase, HDAC1, was identified in 1996 (see, 10 for example, Tauton et al., 1996). Subsequently, two other nuclear mammalian deacetylases were found, HDAC2 and HDAC3 (see, for example, Yang et al., 1996, 1997, and Emiliani et al., 1998). See also, Grozinger et al., 1999; Kao et al., 2000; and Van den Wyngaert et al., 2000. 15 Eleven (11) human HDACs have been cloned so far: HDAC1 (Genbank Accession No. NP_004955) HDAC2 (Genbank Accession No. NP_001518) HDAC3 (Genbank Accession No. 015379) HDAC4 (Genbank Accession No. AAD29046) 20 HDAC5 (Genbank Accession No. NP_005465) HDAC6 (Genbank Accession No. NP_006035) HDAC7 (Genbank Accession No. AAF63491) HDAC8 (Genbank Accession No. AAF73428) HDAC9 (Genbank Accession No. AAK66821) 25 HDAC10 (Genbank Accession No. AAK84023) HDAC 11 (Genbank Accession No. NM_024827 These eleven human HDACs fall in two distinct classes: HDACs 1, 2, 3 and 8 are in class I, and HDACs 4, 5, 6, 7, 9, 10 and 11 are in class II. 30 There are a number of histone deacetylases in yeast, including the following: RPD3 (Genbank Accession No. NP_014069) HDA1 (Genbank Accession No. P53973) HOS1 (Genbank Accession No. Q12214) 35 HOS2 (Genbank Accession No. P53096) HOS3 (Genbank Accession No. Q02959) WO 03/082288 PCT/GB03/01463 -4 There are also numerous plant deacetylases, for example, HD2, in Zea mays (Genbank Accession No. AF254073_1). 5 HDACs function as part of large multiprotein complexes, which are tethered to the promoter and repress transcription. Well characterised transcriptional repressors such as Mad (Laherty et al., 1997), pRb (Brehm et al., 1998), nuclear receptors (Wong et al., 1998) and YY1 (Yang et al., 1997) associate with HDAC complexes to exert their repressor function. 10 The study of inhibitors of histone deacetylases indicates that these enzymes play an important role in cell proliferation and differentiation. The inhibitor Trichostatin A (TSA) (Yoshida et al., 1 990a) causes cell cycle arrest at both G1 and G2 phases (Yoshida and Beppu, 1988), reverts the transformed phenotype of different cell lines, and induces 15 differentiation of Friend leukaemia cells and others (Yoshida et al., 1990b). TSA (and SAHA) have been reported to inhibit cell growth, induce terminal differentiation, and prevent the formation of tumours in mice (Finnin et al., 1999). Trichostatin A (TSA) MeN e MeOH 20 O O Suberoylanilide Hydroxamic Acid (SAHA) ci' H N C OH H II O 0 25 Cell cycle arrest by TSA correlates with an increased expression of gelsolin (Hoshikawa et al., 1994), an actin regulatory protein that is down regulated in malignant breast cancer (Mielnicki et al., 1999). Similar effects on cell cycle and differentiation have been observed with a number of deacetylase inhibitors (Kim et al., 1999). 30 Trichostatin A has also been reported to be useful in the treatment of fibrosis, e.g., liver fibrosis and liver cirrhosis. See, e.g., Geerts et al., 1998.
WO 03/082288 PCT/GB03/01463 -5 Recently, certain compounds that induce differentiation have been reported to inhibit histone deacetylases. Several experimental antitumour compounds, such as trichostatin A (TSA), trapoxin, suberoylanilide hydroxamic acid (SAHA), and phenylbutyrate have 5 been reported to act, at least in part, by inhibiting histone deacetylase (see, e.g., Yoshida et al., 1990; Richon et al., 1998; Kijima et al., 1993). Additionally, diallyl sulfide and related molecules (see, e.g., Lea et al., 1999), oxamflatin (see, e.g., Kim et al., 1999; Sonoda et al., 1996), MS-27-275, a synthetic benzamide derivative (see, e.g., Saito et al., 1999; Suzuki et al., 1999; note that MS-27-275 was later re-named as MS-275), butyrate 10 derivatives (see, e.g., Lea and Tulsyan, 1995), FR901228 (see, e.g., Nokajima et al., 1998), depudecin (see, e.g., Kwon et al., 1998), and m-carboxycinnamic acid bishydroxamide (see, e.g., Richon et al., 1998) have been reported to inhibit histone deacetylases. In vitro, some of these compounds are reported to inhibit the growth of fibroblast cells by causing cell cycle arrest in the G1 and G2 phases, and can lead to the 15 terminal differentiation and loss of transforming potential of a variety of transformed cell lines (see, e.g., Richon et al., 1996; Kim et al., 1999; Yoshida et al., 1995; Yoshida & Beppu, 1988). In vivo, phenybutyrate is reported to be effective in the treatment of acute promyelocytic leukemia in conjunction with retinoic acid (see, e.g., Warrell et al., 1998). SAHA is reported to be effective in preventing the formation of mammary tumours in rats, 20 and lung tumours in mice (see, e.g., Desai et al., 1999). The clear involvement of HDACs in the control of cell proliferation and differentiation suggests that aberrant HDAC activity may play a role in cancer. The most direct demonstration that deacetylases contribute to cancer development comes from the 25 analysis of different acute promyelocytic leukemias (APL). In most APL patients, a translocation of chromosomes 15 and 17 (t(1 5;17)) results in the expression of a fusion protein containing the N-terminal portion of PML gene product linked to most of RARa (retinoic acid receptor). In some cases, a different translocation (t(11;17)) causes the fusion between the zinc finger protein PLZF and RARa. In the absence of ligand, the wild 30 type RARa represses target genes by tethering HDAC repressor complexes to the promoter DNA. During normal hematopoiesis, retinoic acid (RA) binds RARa and displaces the repressor complex, allowing expression of genes implicated in myeloid differentiation. The RARa fusion proteins occurring in APL patients are no longer responsive to physiological levels of RA and they interfere with the expression of the RA 35 inducible genes that promote myeloid differentiation. This results in a clonal expansion of promyelocytic cells and development of leukaemia. In vitro experiments have shown that WO 03/082288 PCT/GB03/01463 -6 TSA is capable of restoring RA-responsiveness to the fusion RARa proteins and of allowing myeloid differentiation. These results establish a link between HDACs and oncogenesis and suggest that HDACs are potential targets for pharmaceutical intervention in APL patients. (See, for example, Kitamura et al., 2000; David et al., 1998; 5 Lin et al., 1998). Furthermore, different lines of evidence suggest that HDACs may be important therapeutic targets in other types of cancer. Cell lines derived from many different cancers (prostate, colorectal, breast, neuronal, hepatic) are induced to differentiate by 10 HDAC inhibitors (Yoshida and Horinouchi, 1999). A number of HDAC inhibitors have been studied in animal models of cancer. They reduce tumour growth and prolong the lifespan of mice bearing different types of transplanted tumours, including melanoma, leukaemia, colon, lung and gastric carcinomas, etc. (Ueda et al., 1994; Kim et al., 1999). 15 Psoriasis is a common chronic disfiguring skin disease which is characterised by well demarcated, red, hardened scaly plaques: these may be limited or widespread. The prevalence rate of psoriasis is approximately 2%, i.e., 12.5 million sufferers in the triad countries (US/Europe/Japan). While the disease is rarely fatal, it clearly has serious detrimental effects upon the quality of life of the patient: this is further compounded by the 20 lack of effective therapies. Present treatments are either ineffective, cosmetically unacceptable, or possess undesired side effects. There is therefore a large unmet clinical need for effective and safe drugs for this condition. Psoriasis is a disease of complex etiology. Whilst there is clearly a genetic component, 25 with a number of gene loci being involved, there are also undefined environmental triggers. Whatever the ultimate cause of psoriasis, at the cellular level, it is characterised by local T-cell mediated inflammation, by keratinocyte hyperproliferation, and by localised angiogenesis. These are all processes in which histone deacetylases have been implicated (see, e.g., Saunders et al., 1999; Bernhard et al., 1999; Takahashi et al., 1996; 30 Kim et al , 2001). Therefore HDAC inhibitors may be of use in therapy for psoriasis. Candidate drugs may be screened, for example, using proliferation assays with T-cells and/or keratinocytes. Thus, one aim of the present invention is the provision of compounds which are potent 35 inhibitors of histone deacetylases (HDACs). There is a pressing need for such WO 03/082288 PCT/GB03/01463 -7 compounds, particularly for use as antiproliferatives, for example, anti-cancer agents, agents for the treatment of psoriasis, etc. Such molecules desirably have one or more of the following properties and/or effects: 5 (a) easily gain access to and act upon tumour cells; (b) down-regulate HDAC activity; (c) inhibit the formation of HDAC complexes; (d) inhibit the interactions of HDAC complexes; (e) inhibit tumour cell proliferation; 10 (e) promote tumour cell apoptosis; (f) inhibit tumour growth; and, (g) complement the activity of traditional chemotherapeutic agents. A number of carbamic acid compounds have been described. 15 Certain classes of carbamic acid compounds which inhibit HDAC are described in Watkins et al., 2002a, 2002b, and 2002c. Piperazino Amides 20 Alpegiani et al., 1999, describe compounds of the following type (Q 2 has backbone=2; is alkylene; is a-substituted) which are proposed to be useful in the treatment of diseases involving matrix metalloproteases (MMPs) and/or tumor necrosis factor a (TNF-a). N0 25 N 0 H "N R 12 R 25 WO 03/082288 PCT/GB03/01463 -8 Alpegiani et al., 1999, also describes the following compound (Q 2 has backbone=2; is alkylene; is a-substituted): OMe 0 N (CH 2
)
3 Example 42 (page 15) N N H O0 H 2 N HN, OH 5 Billedeau et al., 2000, describe compounds of the following type (wherein R 1 is, e.g., phenyl) (Q 2 has backbone=3; is alkylene; is a-substituted), which apparently inhibit procollagen C-proteinase, and are proposed for use in the treatment of fibrotic diseases. 1 H RN HO' N' O N ",-R2 O O=S=O R 10 Broadhurst et al., 1993, describe the following compound (Q 2 has backbone=2; is alkylene; is a-substituted), which apparently inhibits collagenase. OH 00 NH o Compound F (page 9) N N S i-Bu NMe Broadhurst et al., 1995, describe the following compound (Q 2 has backbone=2; is 15 alkylene; is a-substituted), which apparently inhibits collagenase, and is proposed for use in the treatment of cancer, arteriosclerosis and inflammation. OH I O NH 0 Me N N Me Example 18 (page 15) N Me 0 WO 03/082288 PCT/GB03/01463 -9 Hou et al., 2001, describe the following compound (Q 2 has backbone=2; is alkylene; is a-substituted), which apparently inhibits the proteinase gelatinase-A. N' NN 0 0 ,.. . N > OO O^_CO HON H HON Compound a15 (page 5314) H
NH
2 5 Owen et al., 2001, describe the following compound (Q 2 has backbone=2; is alkylene), which apparently inhibits certain MMPs, and is proposed for use in the treatment of inflammation. CI O Example 4 (page 20) HON N 0 H 10 Pratt et al., 2001, describe the following compounds (Q 2 has backbone=2; is alkylene), which apparently have anti-bacterial activity. F Cl Example 41 (page 47) N Example 42 (page 49)N NC) Q 0 0 H H N OH NOH 0 0 15 Piperazino Bisamides A number of hydroxamic acids comprising a piperazine moiety with carbonyl groups adjacent to each nitrogen atom of the piperazine moiety are known.
WO 03/082288 PCT/GB03/01463 -10 Chong et al., 2002 describe the following compound (Q 2 has backbone=2; is alkylene) as an inhibitor of peptide deformylase for use as an antibiotic. O H "N CAS No. 409129-96- 0 P NJ N_, lay 0 0 0 5 Billedeau et al., 2000 describe the following two compounds (Q 2 has backbone=3; is alkylene; is a-substituted) as inhibitors of procollagen C-proteinase for use in the treatment of fibrosis, sclerosis, arthritis and acute respiratory distress syndrome. H.. 0 HO '1 0 NH N N N 0 'S0 CAS No. 279255-56-0P O O 0O 0 HO0 NoN NN I 0> CAS No. 279255-58-2P OO 10 0 Piperazino Sulfonamides Barlaam et al., 2000, describe compounds of the following type (wherein R 3 may be, e.g., 15 phenyl) (Q 2 has backbone=2; is alkylene; is optionally P-substituted), which apparently inhibit MMP-13. R0
R
2 0 0NN O H N? H R 3 N S WO 03/082288 PCT/GB03/01463 -11 Two examples of such compounds (Q 2 has backbone=2; is alkylene) include the following. 0 OH N O H SN Example 3 (page 29) O OO N,0H N N H Example 4 (page 31) N 5 Barlaam et al., 2001, describe compounds of the following type (Q 2 has backbone=2; is alkylene) which apparently inhibit MMP-13 and collagenase 3. 0 NO\ N, OH N \\ H N 0 (CH). x 10 Barta et al., 2000, describe the following compound (Q 2 has backbone=2; is phenylene), which apparently inhibits MMP-2 and MMP-13. 0o, .OH O O N 0 ONJ 0 N HCompound 6k (page 2816) / Compound 6k (page 2816) WO 03/082288 PCT/GB03/01463 -12 Baxter et al., 1999, (Darwin Discovery, UK) describe the following compound (Q 2 has backbone=2; is alkylene), which apparently inhibits certain MMPs. 0 H N OH S 0 N \\ N O Example 35 (page 29) NJ Cl 5 Baxter et al., 2000, (Darwin Discovery, UK) describe compounds of the following type
(Q
2 has backbone=2; is alkylene), which apparently inhibitor certain MMPs. R R2 H 0 OH 'S 0 C N \\ NJ0 CI Bedell et al., 2000, and Bedell et al., 2001, describe compounds of the following type 10 (Q 2 has backbone=2; is phenylene), which apparently inhibit certain MMPs.
R
3 0' 1 O2 NVSR R N O\O 0 ,O N0 N R H WO 03/082288 PCT/GB03/01463 -13 De Crescenzo et al., 2000, describe compounds of the following type (Q 2 has backbone=2; is alkylene), which apparently inhibit certain MMPs.
R
3 0 N H H O N OH 0 NOH .s. 0 0 N N
R
2 R / 5 Hannah et al., 2001, (Darwin Discovery, UK) describe compounds of the following type
(Q
2 has backbone=2; is alkylene; is optionally a-substituted), which apparently inhibit certain MMPs. O SR N OH rN 0
R
2 H R 3.-N-v 10 Martin et al., 2000, describes the following compound (Q 2 has backbone=2; is alkylene), which apparently inhibits certain MMPs. 0 Oe OH N S Ea N N' H NJ Example 8 (page 23) WO 03/082288 PCT/GB03/01463 -14 Owen et al., 2000, (Darwin Discovery, UK) describe compounds of the following type
(Q
2 has backbone=2; is phenylene), which are apparently inhibit certain MMPs. W w 0 O SOH N O H, 0H 0 , X N 0 N X N R OH H 0 Y Y 5 Owen et al., 2000, (Darwin Discovery, UK) also describes the following compound
(Q
2 has backbone=3; is phenylene): 0 H \\ .N, N \\ 0 0 N S O CN Example 64 (page 32) Cl SUMMARY OF THE INVENTION 10 One aspect of the invention pertains to active carbamic acid compounds, as described herein. Another aspect of the invention pertains to active compounds, as described herein, which 15 inhibit HDAC activity. Another aspect of the invention pertains to active compounds, as described herein, which treat conditions which are known to be mediated by HDAC, or which are known to be treated by HDAC inhibitors (such as, e.g., trichostatin A). 20 Another aspect of the invention pertains to active compounds, as described herein, which (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these. 25 Another aspect of the invention pertains to active compounds, as described herein, which are anti-HDAC agents, and which treat a condition mediated by HDAC.
WO 03/082288 PCT/GB03/01463 -15 Another aspect of the invention pertains to active compounds, as described herein, which are anticancer agents, and which treat cancer. 5 Another aspect of the invention pertains to active compounds, as described herein, which are antiproliferative agents, and which treat a proliferative condition. Another aspect of the invention pertains to active compounds, as described herein, which are antipsoriasis agents, and which treat psoriasis. 10 Another aspect of the present invention pertains to a composition comprising a compound, as described herein, and a carrier. Another aspect of the present invention pertains to a composition comprising a 15 compound, as described herein, and a pharmaceutically acceptable carrier. Another aspect of the present invention pertains to methods of inhibiting HDAC in a cell, comprising contacting said cell with an effective amount of an active compound, as described herein, whether in vitro or in vivo. 20 Another aspect of the present invention pertains to methods of (a) regulating (e.g., inhibiting) cell proliferation; (b) inhibiting cell cycle progression; (c) promoting apoptosis; or (d) a combination of one or more of these, comprising contacting a cell with an effective amount of an active compound, as described herein, whether in vitro or in 25 vivo. Another aspect of the present invention pertains to methods of treating a condition which is known to be mediated by HDAC, or which is known to be treated by HDAC inhibitors (such as, e.g., trichostatin A), comprising administering to a subject in need of treatment a 30 therapeutically-effective amount of an active compound, as described herein. Another aspect of the present invention pertains to methods of treating cancer, comprising administering to a subject in need of treatment a therapeutically-effective amount of an active compound, as described herein. 35 WO 03/082288 PCT/GB03/01463 - 16 Another aspect of the present invention pertains to methods of treating a proliferative condition comprising administering to a subject in need of treatment a therapeutically effective amount of an active compound, as described herein. 5 Another aspect of the present invention pertains to methods of treating psoriasis comprising administering to a subject in need of treatment a therapeutically-effective amount of an active compound, as described herein. Another aspect of the present invention pertains to an active compound, as described 10 herein, for use in a method of treatment of the human or animal body by therapy. Another aspect of the present invention pertains to use of an active compound, as described herein, for the manufacture of a medicament for use in the treatment of a condition mediated by HDAC, a condition known to be treated by HDAC inhibitors (such 15 as, e.g., trichostatin A), cancer, a proliferative condition, psoriasis, or other condition as described herein. Another aspect of the present invention pertains to a kit comprising (a) the active compound, preferably provided as a pharmaceutical composition and in a suitable 20 container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active compound. Another aspect of the present invention pertains to compounds obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as 25 described herein. Another aspect of the present invention pertains to compounds obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein. 30 Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein. Another aspect of the present invention pertains to the use of such novel intermediates, 35 as described herein, in the methods of synthesis described herein.
WO 03/082288 PCT/GB03/01463 -17 As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspects of the invention. DETAILED DESCRIPTION OF THE INVENTION 5 Compounds In one aspect, the present invention pertains to carbamic acid compounds of the formula: O I 1 2 2 I Cy-Q-J--N 1 4N-J Q- C-N-OH (1) H wherein: 10 Cy is independently a cyclyl group;
Q
1 is independently a covalent bond or cyclyl leader group; the piperazin-1,4-diyl group is optionally substituted;
J
1 is independently a covalent bond or -C(=O)-; j 2 is independently -C(=O)- or -S(=O)2- ; 15 Q 2 is independently an acid leader group; wherein: Cy is independently:
C
3
-
2 0 carbocyclyl, 20 C 3
.-
2 0 heterocyclyl, or Cs- 2 0 aryl; and is optionally substituted; Q1 is independently: a covalent bond; 25 Cl.
7 alkylene; or Cl_ 7 alkylene-X-CI- 7 alkylene, -X-Cl 7 alkylene, or C 1 l 7 alkylene-X-, wherein X is -0- or -S-; and is optionally substituted;
Q
2 is independently: 30 C 48 .aalkylene; and is optionally substituted; and has a backbone length of at least 4 atoms; or:
Q
2 is independently: WO 03/082288 PCT/GB03/01463 -18 C5_ 20 arylene;
C
5
-
20 arylene-Cl 7 alkylene;
C
1 l 7 alkylene-C5- 2 0 arylene; or,
C
1
.
7 alkylene-C-2 0 arylene-C 1 -7alkylene; 5 and is optionally substituted; and has a backbone length of at least 4 atoms; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. 10 In preferred embodiments, the carbamic acid group, -C(=O)NHOH, is unmodified (e.g., is not an ester). Note that each of the groups -J 1
-Q
1 -Cy and -J 2
-Q
2 -C(=O)NHOH is a monovalent and 15 monodentate species; and that is it not intended that these groups be linked, other than via the N-1 and N-4 atoms, respectively, of the piperazin-1,4-diyl group. The Piperazin-1,4-diyl Group 20 The piperazin-1,4-diyl group is optionally substituted, i.e., unsubstituted or substituted. In one embodiment, the piperazin-1,4-diyl group is unsubstituted (i.e., unsubstituted at the 2-, 3-, 5-, and 6-positions). 25 In one embodiment, the piperazin-1,4-diyl group is substituted (i.e., substituted at one or more the 2-, 3-, 5-, and 6-positions. For example, in one embodiment, the piperazin-1,4-diyl group is substituted (i.e., substituted at one or more the 2-, 3-, 5-, and 6-positions with C4_ 4 alkyl, for example, 30 Me or -Et. For example, in one embodiment, the piperazin-1,4-diyl group is: unsubstituted piperazin-1,4-diyl or 2-methyl-piperazin-1,4-diyl. 35 The piperazin-1,4-diyl group may be in any conformation, including, but not limited to, chair-, boat-, or twist-forms.
WO 03/082288 PCT/GB03/01463 -19 The Linkers, J 1 and J 2 In one embodiment, J 1 is independently a covalent bond. 5 In one embodiment, J 1 is independently -C(=O)-. In one embodiment, J 2 is independently -C(=O)-. In one embodiment, J 2 is independently -S(=0) 2 -. 10 In one embodiment:
J
1 is a covalent bond and J 2 is -C(=O)-; or:
J
1 is -C(=O)- and J 2 is -C(=O)-; or:
J
1 is a covalent bond and J 2 is -S(=0O) 2 -. 15 In one embodiment:
J
1 is a covalent bond and J 2 is -C(=O)-; or:
J
1 is -C(=O)- and J 2 is -C(=O)-. In one embodiment, J 1 is a covalent bond and J 2 is -C(=O)- (and the compounds may be 20 referred to as "piperazino-amides"): 0 0 Cy-Q--N 1 4 N-C-Q- C-N-OH (2) H In one embodiment, J 1 is -C(=O)- and J 2 is -C(=O)- (and the compounds may be referred to as "piperazino-bisamides"): 0 0 0 O O O 1 II II 2 11 Cy-Q-C-N 1 4 N-C-Q- C-N-OH (3) H 25 In one embodiment, J 1 is a covalent bond and J 2 is -S(=O)2- (and the compounds may be referred to as "piperazino-sulfonamides"): O 0 SII 2 II Cy-Q--N 1 4 N-S-Q- C-N-OH (4) 11 H 0 WO 03/082288 PCT/GB03/01463 - 20 In one embodiment, J 1 is -C(=0)- and J 2 is -S(=0) 2 - (and the compounds may be referred to as "piperazino-amide-sulfonamides"): 0 0 0 O OO 1 II II 2 Cy-Q--C-N 1 4 N-S-Q- C-N-OH (5) II H o For the avoidance of doubt, it is intended that, if there is a -C(=O)- group immediately 5 adjacent to the N-1 atom of the piperazin-1-4-diyl group, then that -C(=0)- group must be assigned as J 1 (that is, J 1 is -(C=0)-) and not as part of Q 1 (e.g., as part of an oxo substituted Q 1 group). For example, if the Cy-Q'-J l - group is Ph-CH 2 -C(=O)-, then Cy is Ph-, Q 1 is -CH 2 -, and J 1 is -C(=O)-. 10 Assigning the Cyclyl Group, Cy If, within the group -J'-Q 1 -Cy, there is a plurality of candidate groups satisfying the definition of Cy (referred to as candidate Cy groups), then the candidate Cy group which is furthest from from the N-1 atom of the piperazin-1,4-diyl group is identified as Cy (and 15 referred to as "the relevant Cy group"). In this context, distance (e.g., further, furthest) is measured as the number of chain atoms in the shortest continuous chain linking the groups (i.e., the N-1 atom and Cy). 20 If there is a plurality of furthest candidate Cy groups, then the one (including any substituents) with the largest molecular weight is the relevant one. If there is a plurality of furthest heaviest candidate Cy groups, then the one (excluding any substituents) with the most annular heteroatoms is the relevant one. 25 If there is a plurality of furthest heaviest candidate Cy groups with the most annular heteroatoms, then the one with an IUPAC name which alphabetically precedes the other(s), is the relevant one.
WO 03/082288 PCT/GB03/01463 -21 Some illustrative examples are shown below. pyrazol-3-yl HN-N N1 N1 N 1 Cy -Y MeO Cy/ N imidazol-4-yl If the group, Q 1 , is a cyclyl leader group (i.e., not a covalent bond) and/or J1 is -C(=O)-, 5 the group -Q'-Jl- has a backbone length, as determined by the number of chain atoms in the shortest continuous chain of atoms linking the relevant cyclyl group, Cy, and the N-1 atom of the piperazin-1,4-diyl group. In the following example, -Q'-J'- has a backbone length of 2. N 1 Cy 10 The Cyclyl Group, Cv Cy is independently: C 3
-
20 carbocyclyl, C 3
-
20 heterocyclyl, or C- 20 aryl; and is optionally substituted. 15 In one embodiment, Cy is independently C 3
-
20 carbocyclyl; and is optionally substituted. In one embodiment, Cy is independently monocyclic C 3
.
7 carbocyclyl, and is optionally substituted. 20 In one embodiment, Cy is independently monocyclic Cs.
6 carbocyclyl, and is optionally substituted. In one embodiment, Cy is independently C 3
-
20 carbocyclyl derived from one of the 25 following: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, norbornane, adamantane, cyclopentanone, and cyclohexanone; and is optionally substituted. In one embodiment, Cy is independently C3- 2 0 heterocyclyl; and is optionally substituted.
WO 03/082288 PCT/GB03/01463 - 22 In one embodiment, Cy is independently monocyclic C 3 -7heterocyclyl, and is optionally substituted. 5 In one embodiment, Cy is independently monocyclic C 5
.
6 heterocyclyl, and is optionally substituted. In one embodiment, Cy is independently C 3
.
20 heterocyclyl derived from one of the following: piperidine, azepine, tetrahydropyran, morpholine, azetidine, piperazine, 10 imidazoline, piperazinedione, and oxazolinone; and is optionally substituted. In one embodiment, Cy is independently C5- 20 aryl; and is optionally substituted. In one embodiment, Cy is independently C5- 2 0 carboaryl or C 5
-
20 heteroaryl; and is optionally 15 substituted. In one embodiment, Cy is independently C5- 20 heteroaryl; and is optionally substituted. In one embodiment, Cy is monocyclic C5- 20 heteroaryl; and is optionally substituted. In one embodiment, Cy is monocyclic C 5
-
6 heteroaryl; and is optionally substituted. 20 In one embodiment, Cy is independently C5- 20 carboaryl; and is optionally substituted. In one embodiment, Cy is monocyclic C5.
20 carboaryl; and is optionally substituted. In one embodiment, Cy is monocyclic C 5
-
6 carboaryl; and is optionally substituted. In one embodiment, Cy is phenyl; and is optionally substituted. 25 In one embodiment, Cy is independently C5- 20 aryl derived from one of the following: benzene, pyridine, furan, indole, pyrrole, imidazole, pyrimidine, pyrazine, pyridizine, naphthalene, quinoline, indole, benzimidazole, benzothiofuran, fluorene, acridine, and carbazole; and is optionally substituted. 30 Examples of substituents on Cy include, but are not limited to, those described under the heading "Substituents" below. In one embodiment, the optional substituents on Cy are as defined under the heading 35 "The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents." WO 03/082288 PCT/GB03/01463 - 23 The Cyclyl Group, Cy: Optionally Substituted Phenyl In one embodiment, Cy is independently an optionally substituted phenyl group. 5 In one embodiment, Cy is independently an optionally substituted phenyl group of the formula: 3' 2' RA n 5' 6' wherein n is independently an integer from 0 to 5, and each RA is independently a substituent as defined herein. 10 In one embodiment, Cy is an optionally substituted phenyl group, Q 1 is a covalent bond or a cyclyl leader group, J 1 is a covalent bond, and the compounds have the following formula: 3' 2' 0 - / 2 2 11 RA -N 1 4 N-J Q- C-N-OH (6) A,, \- H n 5' 6' 15 In one embodiment, Cy is an optionally substituted phenyl group, Q 1 is a cyclyl leader group, J 1 is a covalent bond, and the compounds have the following formula: 3- 2' 0 S2 2 II Q-N 1 4 N-J--Q C-N-OH (7) RA - ==/ H n 5' 6' In one embodiment, Cy is an optionally substituted phenyl group, Q 1 is a covalent bond, J 1 is a covalent bond, and the compounds have the following formula: 3' 2' 0 2 2 11 (8) 4'/ )-N 1 4 N-J-Q C-N-OH (8) A "- H n 5' 6' 20 In one embodiment, n is an integer from 0 to 5. In one embodiment, n is an integer from 0 to 4. In one embodiment, n is an integer from 0 to 3. In one embodiment, n is an integer from 0 to 2. 25 In one embodiment, n is 0 or 1.
WO 03/082288 PCT/GB03/01463 - 24 In one embodiment, n is an integer from 1 to 5. In one embodiment, n is an integer from 1 to 4. In one embodiment, n is an integer from 1 to 3. In one embodiment, n is 1 or 2. 5 In one embodiment, n is 5. In one embodiment, n is 4. In one embodiment, n is 3. In one embodiment, n is 2. In one embodiment, n is 1. 10 In one embodiment, n is 0. If the phenyl group has less than the full complement of ring substituents, RA, they may be arranged in any combination. For example, if n is 1, RA may be in the 2'-, 3'-, 4'-, 5'-, or 6'-position. Similarly, if n is 2, the two RA groups may be in, for example, the 2',3'-, 2',4'-, 15 2',5'-, 2',6'-, 3',4'-, or 3',5'-positions. If n is 3, the three RA groups may be in, for example, the 2',3',4'-, 2',3',5'-, 2',3',6'-, or 3',4',5'-positions. In one embodiment, n is 0. 20 In one embodiment, n is 1, and the RA group is in the 4'-position. In one embodiment, n is 2, and one R A group is in the 4'-position, and the other RA group is in the 2'-position. 25 In one embodiment, n is 2, and one R A group is in the 4'-position, and the other RA group is in the 3'-position. The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents 30 Examples of substituents on Cy (e.g., RA), include, but are not limited to, those described under the heading "Substituents" below. Further examples of substituents on Cy (e.g., RA), include, but are not limited to, those described below. 35 WO 03/082288 PCT/GB03/01463 - 25 In one embodiment, each of the substituents on Cy (e.g., each RA), is independently selected from: (1) ester; (2) amido; 5 (3) acyl; (4) halo; (5) hydroxy; (6) ether; (7) C 1
.
7 alkyl, including substituted C 17 alkyl; 10 (8) C5- 20 aryl, including substituted C5.
20 aryl; (9) sulfonyl; (10) sulfonamido; (11) amino; (12) morpholino; 15 (13) nitro; (14) cyano. In one embodiment, each of the substituents on Cy (e.g., each RA), is independently selected from: 20 (1) -C(=O)OR 1 , wherein R 1 is independently C 1
.
7 alkyl as defined in (7); (2) -C(=O)NR 2
R
3 , wherein each of R 2 and R 3 is independently -H or C 1
.
7 alkyl as defined in (7); (3) -C(=O)R 4 , wherein R 4 is independently C1- 7 alkyl as defined in (7) or C5.
2 0 aryl as defined in (8); 25 (4) -F, -Cl, -Br, -I; (5) -OH; (6) -OR, wherein R 5 is independently C 1
.
7 alkyl as defined in (7) or Cs 5
.
20 aryl as defined in (8); (7) C 1
.
7 alkyl, including substituted C 1
-
7 alkyl, e.g., 30 halo-CI.
7 alkyl; amino-C 1
.
7 alkyl (e.g., -(CH 2 )w-amino); carboxy-C 1
.
7 alkyl (e.g., -(CH 2 ),-COOH); hydroxy-Cl_ 7 alkyl (e.g., -(CH 2 )w-OH);
C
1
.
7 alkoxy-Cl.
7 alkyl (e.g., -(CH 2 )w-O-C 1
.
7 alkyl); 35 C6- 20 aryl-C 1
.
7 alkyl; wherein w is 1, 2, 3, or 4; WO 03/082288 PCT/GB03/01463 - 26 (8) C5- 20 aryl, including substituted Cs 5 20 aryl; (9) -SO 2
R
7 , wherein R 7 is independently C 1
_
7 alkyl as defined in (7) or C5- 20 aryl as defined in (8); (10) -SO 2
NR"R
9 , wherein each of R' and R is independently -H or Cl 7 alkyl as defined in 5 (7); (11) -NRioR 11 , wherein each of R"o and R" 1 is indenpendently-H or C 1 _7 alkyl as defined in (7); (12) morpholino; (13) nitro; 10 (14) cyano. In one embodiment, each of the substituents on Cy (e.g., each RA), is independently selected from: (1) -C(=O)OMe, -C(=O)OEt, -C(=O)O(Pr), -C(=O)O(iPr), -C(=O)O(nBu), -C(=O)O(sBu), 15 -C(=O)O(iBu), -C(=O)O(tBu), -C(=O)O(nPe);
-C(=O)OCH
2
CH
2 OH, -C(=O)OCH 2
CH
2 OMe, -C(=O)OCH 2
CH
2 OEt; (2) -(C=O)NH 2 , -(C=O)NMe 2 , -(C=O)NEt 2 , -(C=O)N(iPr) 2 , -(C=O)N(CH 2
CH
2
OH)
2 ; (3) -(C=O)Me, -(C=O)Et, -(C=O)-cHex, -(C=O)Ph; (4) -F, -Cl, -Br, -I; 20 (5) -OH; (6) -OMe, -OEt, -O(iPr), -O(tBu), -OPh;
-OCF
3 , -OCH 2
CF
3 ;
-OCH
2
CH
2 OH, -OCH 2
CH
2 OMe, -OCH 2
CH
2 OEt;
-OCH
2
CH
2
NH
2 , -OCH 2
CH
2 NMe 2 , -OCH 2
CH
2 N(iPr) 2 ; 25 -OPh, -OPh-Me, -OPh-OH, -OPh-OMe, O-Ph-F, -OPh-CI, -OPh-Br, -OPh-I; (7) -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe;
-CF
3 , -CH 2
CF
3 ;
-CH
2
CH
2 OH, -CH 2
CH
2 OMe, -CH 2
CH
2 OEt;
-CH
2
CH
2
NH
2 , -CH 2
CH
2 NMe 2 , -CH 2
CH
2 N(iPr) 2 ; 30 -CH 2 -Ph; (8) -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-F, -Ph-Cl, -Ph-Br, -Ph-I; (9) -SO 2 Me, -SO 2 Et, -SO 2 Ph; (10) -SO 2
NH
2 , -SO 2 NMe 2 , -SO 2 NEt 2 ; (11) -NMe 2 , -NEt 2 ; 35 (12) morpholino; (13) -NO 2
;
WO 03/082288 PCT/GB03/01463 -27 (14) -CN. In one embodiment, each of the substituents on Cy (e.g., each RA), is independently selected from: 5 -C(=O)OMe, -C(=O)O(Pr), -C(=O)NHMe, -C(=O)Et, C(=O)Ph,
-OCH
2
CH
2 OH, -OMe, -OPh, -nPr, iPr, -CF 3 , -CH 2
CH
2 OH, -CH 2
CH
2 NMe 2 , -Ph, -Ph-F, -Ph-CI,
-SO
2 Me, -SO 2 Me 2 , -NMe 2 , 10 -F, -Cl, -Me, -Et, -OMe, -OEt, -CH 2 -Ph, -O-CH 2 -Ph. In one embodiment, each of the substituents on Cy (e.g., each RA), is independently selected from: -F, -CI, -Me, -Et, -OMe, -OEt, -Ph, -OPh, -CH 2 -Ph, -O-CH 2 -Ph. 15 Examples of some preferred substituents on Cy (e.g., RA), include, but are not limited to, the following: fluoro, chloro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, cyano, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, trifluoromethoxy, phenoxy, methylthio, trifluoromethylthio, hydroxymethyl, amino, dimethylamino, diethylamino, 20 morpholino, amido (unsubstituted, i.e., -CONH 2 ), acetamido, acetyl, nitro, sulfonamido (unsubstituted, i.e., -SO 2
NH
2 ), and phenyl. The Cyclyl Leader Group, Q 1 25 In one embodiment, Q 1 is independently: a covalent bond; or a cyclyl leader group; and is optionally substituted. 30 In one embodiment, Q 1 is independently: a covalent bond. In one embodiment, Q 1 is independently: a cyclyl leader group; 35 and is optionally substituted.
WO 03/082288 PCT/GB03/01463 - 28 In one embodiment, Q 1 is independently: a covalent bond;
C
1 l 7 alkylene; or
C
1 l 7 alkylene-X-C 17 alkylene, -X-CI_ 7 alkylene, or C 17 alkylene-X-; 5 wherein X is -0- or -S-; and is optionally substituted. In one embodiment, Q 1 is independently: a covalent bond; or 10 a C 1
.
7 alkylene group; and is optionally substituted. In one embodiment, Q' is independently: a C 1
.
7 alkylene group; 15 and is optionally substituted. In one embodiment, Q 1 is independently:
C.
7 alkylene-X-Cl 7 alkylene, -X-C 17 alkylene, or Cl_ 7 alkylene-X-; wherein X is -0- or -S-; 20 and is optionally substituted. In one embodiment, in the above alkylene groups, each alkylene group is independently: (a) a saturated C 1
.
7 alkylene group; or: (b) a partially unsaturated C 2
.
7 alkylene group; or: 25 (c) an aliphatic C 1 7 alkylene group; or: (d) a linear C 1 7 alkylene group; or: (e) a branched C 2 -7alkylene group; or: (f) a saturated aliphatic C 1
_
7 alkylene group; or: (g) a saturated linear C 1
.
7 alkylene group; or: 30 (h) a saturated branched C 27 alkylene group; or: (i) a partially unsaturated aliphatic C 2 -7alkylene group; or: (j) a partially unsaturated linear C 2
.
7 alkylene group; or: (k) a partially unsaturated branched C 2 -7alkylene group; and is optionally substituted. 35 WO 03/082288 PCT/GB03/01463 -29 In one embodiment, the above alkylene groups have a maximum number of carbon atoms of 4, e.g., Cl-4alkylene, C 2 -4alkylene. In one embodiment, the above alkylene groups have a maximum number of carbon atoms 5 of 3, e.g., CI.
3 alkylene, C 2 -3alkylene. In one embodiment, Q 1 is selected so that the N-1 atom of the piperazin-1,4-diyl group is not connected to a carbon atom which is connected to another carbon atom via a non aromatic carbon-carbon double bond (i.e., C=C). That is, the N-1 atom of the piperazin 10 1,4-diyl group is not adjacent to a non-aromatic carbon-carbon double bond (i.e., C=C). In this way, groups such as -CH=CH- and -CH 2 -CH=CH- are excluded from Q 1 , but groups such as -CH=CH-CH 2 - are not. Additional embodiments include other embodiments described herein (e.g., those described above) further limited by this restriction upon Q 1 . 15 The Cyclyl Leader Group, Q': Covalent Bond In one embodiment:
Q
1 is independently a covalent bond; 20 J 1 is independently a covalent bond;
J
2 is independently -C(=O)-. In one embodiment:
Q
1 is independently a covalent bond; 25 J' is independently -C(=O)-; j 2 is independently -C(=O)-. In one embodiment: Q' is independently a covalent bond; 30 J 1 is independently a covalent bond; j 2 is independently -S(=0) 2 -. In one embodiment:
Q
1 is independently a covalent bond; 35 J 1 is independently -C(=O)-;
J
2 is independently -S(=O) 2
-.
WO 03/082288 PCT/GB03/01463 - 30 The Cyclyl Leader Group, Q': Backbone Length The group -J'-Q 1 - has a backbone length, as determined by the number of chain atoms in 5 the shortest continuous chain of atoms linking the relevant Cy group and the N-1 atom of the piperazin-1,4-diyl group. In one embodiment, the group -J'-Q'- has a backbone of: from 1 to 7 atoms; 10 from 1 to 6 atoms; from 1 to 5 atoms; from 1 to 4 atoms; or, from 1 to 3 atoms. 15 In one embodiment, the group -J'-Ql- has a backbone of at least 2 atoms. In this way, groups such as methylene (-CH 2 -) and substituted methylene (-CR 2 - and -CHR-) are excluded. In one embodiment, the group -J'-Q- has a backbone of at least 3 atoms. 20 In one embodiment, the group -J'-Ql- has a backbone of at least 4 atoms. In one embodiment, the group -J 1 -Q- has a backbone of at least 5 atoms. In one embodiment, the group -J'-Ql- has a backbone of: from 2 to 7 atoms; 25 from 2 to 6 atoms; or, from 2 to 5 atoms. In one embodiment, the group -J 1 -Ql- has a backbone of: from 3 to 7 atoms; 30 from 3 to 6 atoms; or, from 3 to 5 atoms. In one embodiment, the group -J'-Ql- has a backbone of: from 4 to 7 atoms; 35 from 4 to 6 atoms; or, from 4 to 5 atoms.
WO 03/082288 PCT/GB03/01463 -31 In one embodiment, the group -J'-Q'- has a backbone of 1 atom. In one embodiment, the group -J'-Q- has a backbone of 2 atoms. In one embodiment, the group -J'-Q 1 - has a backbone of 3 atoms. 5 In one embodiment, the group -J'-Ql- has a backbone of 4 atoms. In one embodiment, the group -J 1 -Q- has a backbone of 5 atoms. In one embodiment, the backbone of "atoms" is a backbone of "carbon atoms." 10 Note that, for embodiments which are characterised by, or further characterised by, a backbone length limitation, corresponding changes in the description of that embodiment may be implicit. For example, for an embodiment wherein (a) Q 1 is a partially unsaturated
C
2 -7alkylene group and (b) Q' has a backbone of 4 carbon atoms, the term "C 2 -7alkylene" group is necessarily, and implicitly, interpreted as "C 4
-
7 alkylene." 15 The Cyclyl Leader Group, Q 1 : Substituents In one embodiment, Q 1 , if other than a covalent bond, is unsubstituted. In one embodiment, Q 1 , if other than a covalent bond, is optionally substituted. 20 In one embodiment, Q 1 , if other than a covalent bond, is substituted. Examples of substituents on Q 1 include, but are not limited to, those described under the heading "Substituents" below. 25 In one embodiment, substituents on Q 1 , if present, are as defined under the heading "The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents." In one embodiment, substituents on Q 1 , if present, are independently: halo, hydroxy, ether (e.g., C 1
-
7 alkoxy), Co- 20 aryl, acyl, amino, amido, acylamido, or oxo. 30 In one embodiment, substituents on Q 1 , if present, are independently: -F, -CI, -Br, -I, -OH, -OMe, -OEt, -OPr, -Ph, -NH 2 , -CONH 2 , or =0. In one embodiment, substituents on Q 1 , if present, are independently -OH or -Ph. 35 In one embodiment, substituents on Q 1 , if present, are independently -Ph.
WO 03/082288 PCT/GB03/01463 - 32 For example, in one embodiment, Q' is unsubstituted methylene, and is -CH 2 -; in one embodiment, Q 1 phenyl (-Ph) substituted methylene, and is -CH(Ph)-. 5 For example, in one embodiment, Q 1 is unsubstituted ethylene, and is -CH 2
-CH
2 -; in one embodiment, Q 1 is oxo (=0) substituted ethylene, and is -C(=O)-CH 2 -; in one embodiment, Q 1 is hydroxy (-OH) substituted ethylene, and is -CH(OH)-CH 2 -; in one embodiment, Q 1 is phenyl (-Ph) substituted ethylene, and is -CH 2 CH(Ph)-. 10 Again, for the avoidance of doubt, it is intended that, if there is a -C(=O)- group immediately adjacent to the N-1 atom of the piperazin-1-4-diyl group, then that -C(=O) group must be assigned as J 1 (that is, J 1 is -(C=0)-) and not as part of Q 1 (e.g., as part of an oxo-substituted Q 1 group). For example, if the Cy-Q 1
-J
1 - group is Ph-CH 2 -C(=0)-, then Cy is Ph-, Q 1 is -CH 2 -, and J 1 is -C(=0)-. 15 The Cyclyl Leader Group, Q': Alkylene: Certain Embodiments Note that, for embodiments excluding, e.g., a covalent bond, certain backbone lengths, absence of adjacent carbon-carbon double bonds, etc., it is to be understood that the 20 corresponding species listed below are similarly excluded from the respective embodiments discussed below. In one embodiment, Q 1 is independently selected from the following: 25 a covalent bond;
-CH
2 -, -(CH 2
)
2 -, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2
)
5 -, -(CH 2
)
6 -, -(CH 2
)
7 -;
-CH(CH
3 )-; 30 -CH(CH 3
)CH
2 -, -CH 2
CH(CH
3 )-;
-CH(CH
3
)CH
2
CH
2 -, -CH 2
CH(CH
3
)CH
2 -, -CH 2
CH
2 CH(CHa)-;
-CH(CH
3
)CH
2
CH
2
CH
2 -, -CH 2
CH(CH
3 )CHzCH 2 -, -CH 2
CH
2 CH(CHa)CH 2 -,
-CH
2
CH
2
CH
2
CH(CH
3 )-;
-CH(CH
3
)CH
2
CH
2
CH
2
CH
2 -, -CH 2
CH(CH
3
)CH
2
CH
2
CH
2 -, 35 -CH 2
CH
2
CH(CH
3
)CH
2
CH
2 -, -CH 2
CH
2
CH
2 CH(CHa)CH 2 -, -CH 2
CH
2
CH
2
CH
2 CH(CHa)-,
-CH(CH
3
)CH
2
CH
2
CH
2
CH(CH
3
)-;
WO 03/082288 PCT/GB03/01463 - 33 -CH (CH 2 CHa)-;
-CH(CH
2
CH
3
)CH
2 -, -CH 2
CH(CH
2
CH
3 )-;
-CH(CH
2
CH
3
)CH
2
CH
2 -, -CH 2 CH(0H 2 0H 3
)CH
2 -, -CH 2
CH
2
CH(CH
2
CH
3 )-; 5 -CH(CH 2
CH
3
)CH
2
GH
2
CH
2 -, -CH 2
CH(CH
2
CH
3
)CH
2
CH
2 -,
-CH
2
CH
2
CH(CH
2
CH
3
)CH
2 -, -CH 2
CH
2
CH
2
CH(CH
2
CH
3 )-;
-CH(CH
2
CH
3
)CH
2
CH
2
CH
2
CH
2 -, -CH 2 CH(0H 2 0H 3
)CH
2
CH
2
CH
2 -,
-CH
2
CH
2
CH(CH
2
CH
3
)CH
2
CH
2 -, -CH 2
CH
2
CH
2
CH(CH
2
CH
3
)CH
2 -,
-CH
2
CH
2
CH
2
CH
2
CH(CH
2
CH
3 )-; 10 -CH=CH-;
-CH=CHCH
2 -, -CH 2 CH=CH-;
-CH=CHCH
2
CH
2 -, -CH 2
CH=CHCH
2 -, -CH 2
CH
2 CH=CH-;
-CH=CHCH
2
CH
2
GH
2 -, -CH 2
CH=CHCH
2
CH
2 -, -CH 2
CH
2
CH=CHCH
2 -, 15 -CH 2
CH
2
CH
2 CH=CH-;
-CH=CHCH
2
CH
2
GH
2
CH
2 -, -CH 2
CH=CHCH
2
CH
2
CH
2 -, -CH 2
CH
2
CH=CHCH
2
CH
2 -,
-CH
2
CH
2
CH
2
CH=CHCH
2 -, -CH 2
CH
2
CH
2
CH
2 CH=CH-; .- C(CH 3 )0CH-, -CH=C(CH 3 )-; 20 -C(CH 3
)=CHCH
2 -, -CH=C(0H 3
)CH
2 -, -CH=CHCH(CH 3 )-;
-CH(CH
3 )CH=CH-, -CH 2
C(CH
3 )=CH-, -CH 2
CH=C(CH
3 )-; -CH=CHCH=-CH-;
-CH=CHCH=CHCH
2 -, -CH 2 CH=CHCH=CH-, -CH=CHCH 2 CH=CH-; 25 -CH=CHCH=CHCH 2
CH
2 -, -CH=CHCH 2
CH=CHCH
2 -, .- CH=CHCH 2
CH
2 CH=CH-,
-CH
2
CH=CHCH=CHCH
2 -, -CH 2
CH=CHCH
2 CH=CH-, -CH 2
CH
2 CH=CHCH=CH-;
-C(CH
3 )=CHCH=CH-, -CH=C(CH 3 )CH=CH-, -CH=CHC(0H 3 )=CH-,
-CH=CHCH=C(CH
3 )-; 30 .- C=-CCH 2 -, -GH 2 C=C-; -C=CCH(CH 3 )-, -CH(CH 3 )C=C-;
-C=-CCH
2
CH
2 -, -CH 2
C=ECCH
2 -, -CH 2
CH
2 C=C-;
-C=-CCH(CH
3
)CH
2 -, -C=ECCH 2 CH (CH 3 )-; 35 -CH(CH 3
)C=ECCH
2 -, -CH 2
C=CCH(CH
3 )-;
-CH(CH
3
)CH
2 GEC-, -CH 2 CH (CH 3
)C=C-;
WO 03/082288 PCT/GB03/01463 -34 -C-ECCH=CH-, -CH=CHC=C-, -C=CC=C-;
-CC
2 CH2 2
CH
2 -, -CH 2
CH
2
CH
2 C=C-;
-C=CCH
2 H2CH 2
CH
2 -, -CH 2
CH
2
CH
2
CH
2 C=C-; -C=ECCH=CHCH=CH-, -CH=CHC=EC-CH=CH-, -CH=CHCH=CHC=C-; 5
-C(CH
3 )=CHC=C-, -CH=C(CH 3 )C-C-, -CECC(CH 3 )=CH-, -CECCH=C(CH 3 )-. In one embodiment, Q 1 is selected from: a covalent bond; 10 -CH 2 -, -(CH 2
)
2 -, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2
)
5 -, -(CH 2
)
6 -;
-CH(CH
3
)CH
2
CH
2
CH
2
CH
2 -, -CH 2
CH(CH
3
)CH
2
CH
2
CH
2 -,
-CH
2
CH
2
CH
2
CH(CH
3
)CH
2 -, -CH 2 H2CH 2
CH
2
CH(CH
3 )-; -CH=CH-;
-CH=CHCH
2 -, -CH=C(Me)CH 2 -; 15 -CH=CH-CH=CH-;
-CH=CH-CH=CHCH
2 -, -CH=CHCH 2
CH
2
CH
2 -, -CH 2
CH
2 CH2CH=CH-;
-CH=CHCH
2
CH
2
CH
2
CH
2 -, -CH 2
CH
2
CH
2
CH
2 CH=CH-;
-C(CH
3 )=CHCH=CH-, -CH=C(CHa)CH=CH-, -CH=CHC(CH 3 )=CH-,
-CH=CHCH=C(CH
3 )-; 20 In one embodiment, Q 1 is selected from: a covalent bond;
-CH
2 -, -(CH 2
)
2 -, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2
)
5 -, -CH=CH-; 25 -CH=CHCH 2 -, -CH=C(Me)CH 2 -; -CH=CH-CH=CH-;
-C(CH
3 )=CHCH=CH-, -CH=C(CH 3 )CH=CH-, -CH=CHC(CH 3 )=CH-,
-CH=CHCH=C(CH
3 )-;
-CH=CHCH
2
CH
2
CH
2 -, -CH 2
CH
2
CH
2 CH=CH-. 30 In one embodiment, Q 1 is independently selected from: a covalent bond;
-CH
2 -, -(CH 2
)
2 -, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2
)
5 -;
-CH=CHCH
2 -; 35 -CH=C(Me)CH 2 -; and,
-CH=CH-CH=CHCH
2
-.
WO 03/082288 PCT/GB03/01463 - 35 In one embodiment, Q 1 is independently selected from: a covalent bond;
-CH
2 -; 5 -CH 2
CH
2 -;
-CH
2
CH
2
CH
2 -;
-CH=CHCH
2 -; -CH=C(Me)CH 2 -; and,
-CH=CH-CH=CHCH
2 -. 10 In one embodiment, Q' is independently selected from: a covalent bond;
-CH
2 -; -CH(*Ph)-; 15 -CH 2
CH
2 -; -CH(*Ph)CH 2 -;
-CH
2 CH(*Ph)-;
-CH
2
CH
2
CH
2 -;
-CH=CHCH
2 -; 20 -CH=C(Me)CH 2 -; and,
-CH=CH-CH=CHCH
2 -; wherein * indicates that the group (e.g., Ph) is optionally substituted with one or more substituents as defined above under the heading "The Cyclyl Group, Cy: Optionally 25 Substituted Phenyl: Substituents." The Cyclyl Leader Group, Q 1 : Ethers and Thioethers: Certain Embodiments Note that, for embodiments excluding, e.g., a covalent bond, certain backbone lengths, 30 absence of adjacent carbon-carbon double bonds, etc., it is to be understood that the corresponding species listed below are similarly excluded from the respective embodiments discussed below. In one embodiment, Q 1 is independently selected from the following: 35 -(CH 2 )aX-(CH 2 )b wherein X is -0- or -S- and WO 03/082288 PCT/GB03/01463 - 36 a and b are each independently 1, 2, 3, 4, 5, 6, or 7; and a+b is at least 1. In one embodiment, Q 1 is independently selected from the following: 5 -O-(CH 2 )a
-S-(CH
2 )a
-(CH
2 )a-O
-(CH
2 )a-S
-(CH
2 )a-O-(CH 2 )b 10 -(CH 2 )a-S-(CH 2 )b wherein a and b are each independently 1, 2, 3, 4, 5, 6, or 7. In one embodiment, Q 1 is independently selected from the following: -- OCH 2 -; -O-CH 2
CH
2 -; -O-CH 2
CH
2
CH
2 -; 15 -S-CH 2 -; -S-CH 2
CH
2 -; -S-CH 2
CH
2
CH
2 -;
-CH
2 -O-; -CH 2
CH
2 -O-; -CH 2
CH
2
CH
2 -O-;
-CH
2 -S-; -CH 2
CH
2 -S-; -CH 2
CH
2
CH
2 -S-; 20 -CH 2
-O-CH
2 -; -CH 2
-O-CH
2
CH
2 -; -CH 2
CH
2
-O-CH
2 -; and
-CH
2
CH
2
-O-CH
2
CH
2 -. The Group -Q'-J'-: Certain Embodiments 25 In one embodiment, the group -Q 1 -Jl- has a formula selected from:
-CH
2 -; -CH(*Ph)-;
-CH
2
CH
2 -; 30 -CH 2 CH(*Ph)-; -CH(*Ph)CH 2 -;
-CH
2
CH
2
CH
2 -; -C(=O)-; 35 -CH2-C(=O)-; -CH(*Ph)-C(=O)-; WO 03/082288 PCT/GB03/01463 -37
-CH
2
CH
2 -C(=0)-; -- OCH 2 -; -0-CH 2
CH
2 -; 5 -CH2-O-;
-CH
2
CH
2 -O-; and,
-O-CH
2 -C(=O)-. 10 wherein * indicates that the group (e.g., Ph) is optionally substituted with one or more substituents as defined above under the heading "The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents." The Group Cy-Q'-: Certain Embodiments 15 In one embodiment, the group Cy-Q'- has a formula selected from: *Ph-; *Ph-CH2-; (*Ph)2CH-; 20 *Ph-CH2CH2-; (*Ph)2-CH2CH2-; *Ph-CHzCH(*Ph)-; *Ph-CH2CH2CH2-; *Ph-CH=CHCH2-; 25 *Ph-CH=C(Me)CH2-; *Ph-CH=CHCH=CHCH2-; (*pyrid-3-yl)-CH=CH CHz-; and, (*cyclohexyl)-CH2CH2-; 30 wherein * indicates that the group (e.g., Ph, pyrid-3-yl, cyclohexyl) is optionally substituted with one or more substituents as defined above under the heading "The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents." In one embodiment, * indicates that the group (e.g., Ph, pyrid-3-yl, cyclohexyl) is 35 optionally substituted with one or more of: -F, -CI, -Br, -I, -OH, -OMe, -OEt, -OPr, -Ph,
-NH
2 , and -CONH 2
.
WO 03/082288 PCT/GB03/01463 - 38 The Acid Leader Group, Q 2 The acid leader group, Q 2 , is independently: 5
C
4
.
8 alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms; 10 or: C5- 20 oarylene; C5- 20 arylene-C 1 -7alkylene; Cl.
7 alkylene-Cs- 2 0 arylene; or,
C
1 .7alkylene-C5- 20 oarylene-C 1
-
7 alkylene; and is optionally substituted; 15 and has a backbone length of at least 4 atoms. In one embodiment, the acid leader group, Q 2 , is independently:
C
4 .-alkylene; and is optionally substituted; 20 and has a backbone length of at least 4 atoms. In one embodiment, the acid leader group, Q 2 , is independently: C5- 20 arylene; Cs- 20 arylene-C 1 l 7 alkylene; 25 C 1 l 7 alkylene-C5- 2 0 oarylene;
C
1
.
7 alkylene-C5- 20 oarylene-Cl 7 alkylene; or, and is optionally substituted; and has a backbone length of at least 4 atoms. 30 The Acid Leader Group, Q 2 : Backbone Length The acid leader group, Q 2 , has a backbone length, as determined by the number of chain atoms in the shortest continuous chain of atoms linking the N-4 atom of the piperazin-1,4 diyl group and the carbamic acid group, -C(=O)NHOH. 35 WO 03/082288 PCT/GB03/01463 - 39 If Q 2 is alkylene, Q 2 necessarily has a backbone of at least 1 atom. Some examples are shown below. backbone length = 4 backbone length = 5 backbone length = 6 5 If Q 2 is arylene, arylene-alkylene, alkylene-arylene, alkylene-arylene-alkylene,
Q
2 necessarily has a backbone of at least 2 atoms. Some examples are shown below. backbone length = 2 backbone length = 8 Without wishing to be bound to any particular theory, it is believed that Q 2 groups with 10 shorter backbone lengths prevent or reduce the interaction of the carbamic acid group (-C(=O)NHOH) with HDAC (or its complexes), and thereby reduce the compound's activity as an HDAC inhibitor. In one embodiment, Q 2 has a backbone of at least 4 atoms. 15 In one embodiment, Q 2 has a backbone of at least 5 atoms. In one embodiment, Q 2 has a backbone of at least 6 atoms. In one embodiment, Q 2 has a backbone of: from 4 to 8 atoms; 20 from 4 to 7 atoms; from 4 to 6 atoms; or, from 4 to 5 atoms. In one embodiment, Q 2 has a backbone of: 25 from 5 to 8 atoms; or from 5 to 7 atoms; or from 5 to 6 atoms. In one embodiment, Q 2 has a backbone of from 5 to 6 atoms. 30 WO 03/082288 PCT/GB03/01463 -40 In one embodiment, Q 2 has a backbone of 4 atoms. In one embodiment, Q 2 has a backbone of 5 atoms. In one embodiment, Q 2 has a backbone of 6 atoms. In one embodiment, Q 2 has a backbone of 7 atoms. 5 In one embodiment, Q 2 has a backbone of 8 atoms. In one embodiment, the backbone of "atoms" is a backbone of "carbon atoms." Note that, for embodiments which are characterised by, or further characterised by, a 10 backbone length limitation, corresponding changes in the description of that embodiment may be implicit. For example, for an embodiment wherein (a) Q 2 is a partially unsaturated
C
2 -8alkylene group and (b) Q 2 has a backbone of 4 carbon atoms, the term "C 28 alkylene" group is necessarily, and implicitly, interpreted as "C 4 -8alkylene." 15 The Acid Leader Group, Q 2 : Substitution In one embodiment, Q 2 is unsubstituted. In one embodiment, Q 2 is optionally substituted. In one embodiment, Q 2 is substituted. 20 The backbone atoms of the acid leader group, Q 2 , which link J and the carbamic acid group (-C(=O)NHOH), are denoted a, 3, y, 6, etc., starting with the backbone atom adjacent to the carbamic acid group. Some examples are illustrated below. O0 J ,
-
OH
Q
2 is alkylene N 0 H ianOH 7 N H Q2 is arylene 8H WO 03/082288 PCT/GB03/01463 -41
Q
2 is arylene-alkylene
N
O H y N,.0H
Q
2 is alkylene-arylene 6 H
Q
2 is alkylene-arylene-alkylene J O H H Without wishing to be bound to any particular theory, it is believed that groups (e.g., substituents), particularly bulky groups (e.g., substituents), at the a-position, or at either or both of the a- and P -positions, prevent or reduce the interaction of the carbamic acid 5 group (-C(=O)NHOH) with HDAC (or its complexes), and thereby reduce the compound's activity as an HDAC inhibitor. In one embodiment, Q 2 is, additionally, unsubstituted at the a-position. 10 In one embodiment, Q 2 is, additionally, unsubstituted at the a-position and unsubstituted at the -position. Note that, in some embodiments, Q 2 may have a non-linear alkylene group (for example, a branched alkylene) adjacent to the carbamic acid group. An example, wherein Q 2 is a 15 branched saturated C-alkylene, having a methyl group at the a-position, is shown below. Although there is a group (i.e., a methyl group) at the a-position, such compounds are unsubstituted at the a-position, because the a-methyl group itself is considered to be part of the unsubstituted Q 2 . Another example, wherein Q 2 is a branched saturated
C
6 -alkylene, having an amino group at the a-position and a methyl group at the P3-position, 20 is shown below; such compounds are a-substituted, -unsubstituted. Me O OO i H N JN0 J IOH Me In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4 -8alkylene,
C
5
-
2 0 oarylene-C 1 -7alkylene, C 1 l 7 alkylene-C5- 20 arylene-Cl 7 alkylene) having an alkylene group 25 adjacent to the carbamic acid group, Q 2 is, additionally, unsubstituted at the a-position.
WO 03/082288 PCT/GB03/01463 -42 In one embodiment, in which Q 2 is a group as defined herein (e.g., C4-8alkylene, Cs 5
-
20 arylene-Cs_ 7 alkylene, C 1 7 alkylene-C 5
-
2 0 arylene-Cs_ 7 alkylene) having an alkylene group adjacent to the carbamic acid group, that adjacent alkylene group has a -CH 2 - or =CH group adjacent to the carbamic acid group (that is, at the a-position). 5 In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4 -8alkylene,
C
5
-
2 0 oarylene-C 1 -7alkylene, C 1
.
7 alkylene-Cs 5
-
20 arylene-C 1 7 alkylene) having an alkylene group adjacent to the carbamic acid group, that adjacent alkylene group has a -CH 2 - group adjacent to the carbamic acid group (that is, at the a-position). 10 In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4 -8alkylene, C5- 20 oarylene-Cl-7alkylene, C 1
-
7 alkylene-Cs.
2 oarylene-C.-7alkylene) having an alkylene group adjacent to the carbamic acid group, that adjacent alkylene group has a =CH- group adjacent to the carbamic acid group (that is, at the a-position). 15 In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4
-
8 alkylene,
C
5
.
20 oaryiene-Cl 7 alkylene, C1.
7 alkylene-C 5
-
20 arylene-C 1 -7alkylene) having an alkylene group adjacent to the carbamic acid group, Q 2 is, additionally, unsubstituted at the a-position and unsubstituted at the 3 -position. 20 In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4 -8alkylene,
C
5
-
20 oarylene-C 1 -7alkylene, C 1
-
7 alkylene-C 5
-
20 arylene-C 1
.
7 alkylene) having an alkylene group adjacent to the carbamic acid group, that adjacent alkylene group has a -CH 2
CH
2 -, -CH=CH-, or -C-C- group adjacent to the carbamic acid group (that is, at the 25 a,p1-position). In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4
_
8 alkylene,
C
5
-
2 0 oarylene-C 1 -7alkylene, C4 7 alkylene-C5-20arylene-C 1 -7alkylene) having an alkylene group adjacent to the carbamic acid group, that adjacent alkylene group has a -CH 2
CH
2 - or 30 -CH=CH- group adjacent to the carbamic acid group (that is, at the a,3-position). In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4
-
8 alkylene,
C
5
-
20 arylene-C 1 -7alkylene, Cl- 7 alkylene-C5- 20 oarylene-C 1 -7alkylene) having an alkylene group adjacent to the carbamic acid group, that adjacent alkylene group has a -CH 2
CH
2 - group 35 adjacent to the carbamic acid group (that is, at the a,13-position).
WO 03/082288 PCT/GB03/01463 -43 In one embodiment, in which Q 2 is a group as defined herein (e.g., C 4 -8alkylene, C5-2 0 arylene-C 1
.
7 alkylene, CI.
7 alkylene-C5- 20 arylene-C 1 7 alkylene) having an alkylene group adjacent to the carbamic acid group, that adjacent alkylene group has a -CH=CH- group adjacent to the carbamic acid group (that is, at the a,13-position). 5 Examples of substituents on Q 2 include, but are not limited to, those described under the heading "Substituents" below. In one embodiment, the optional substituents on Q2 are as defined under the heading 10 "The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents." The Acid Leader Group, Q2: Alkylene In one embodiment, the acid leader group, Q 2 , is C 48 alkylene, and is optionally 15 substituted, and has a backbone length of at least 4 atoms. In one embodiment, Q2 is independently a saturated C 4 _salkylene group. In one embodiment, Q 2 is independently a partially unsaturated C 4
-
8 alkylene group. 20 In one embodiment, Q 2 is independently an aliphatic C 4 -salkylene group In one embodiment, Q 2 is independently a linear C 4
-
8 alkylene group. 25 In one embodiment, Q2 is independently a branched C 4 -8alkylene group. In one embodiment, Q 2 is independently an alicyclic C 4 -8alkylene group. In one embodiment, Q 2 is independently a saturated aliphatic C 4
.
8 alkylene group. 30 In one embodiment, Q 2 is independently a saturated linear C 4 8alkylene group. In one embodiment, Q2 is independently a saturated branched C 4 -8alkylene group. 35 In one embodiment, Q2 is independently a saturated alicyclic C 4 -8alkylene group.
WO 03/082288 PCT/GB03/01463 - 44 In one embodiment, Q 2 is independently a partially unsaturated aliphatic C4-8alkylene group. In one embodiment, Q 2 is independently a partially unsaturated linear C4_8alkylene group. 5 In one embodiment, Q 2 is independently a partially unsaturated branched C 4
-
8 alkylene group. In one embodiment, Q 2 is independently a partially unsaturated alicyclic C4_ 8 alkylene 10 group. Note that, for embodiments excluding, e.g., certain backbone lengths, absence of adjacent carbon-carbon double bonds, etc., it is to be understood that the corresponding species listed below are similarly excluded from the respective embodiments discussed 15 below. In one embodiment, Q 2 is independently selected from:
-(CH
2
)
4 -, -(CH 2
)
5 -, -(CH 2
)
6 -, -(CH 2
)
7 -, -(CH 2
)
8 -; 20
-CH(CH
3
)CH
2
CH
2
CH
2 -, -CH 2
CH(CH
3 )CHzCH 2 -, -CH 2
CH
2
CH(CH
3
)CH
2 -,
-CH
2
CH
2
CH
2
CH(CH
3 )-;
-CH(CH
3
)CH
2
CH
2
CH
2
H
2 -, -CH 2 CH(CHa)CH 2
CH
2
CH
2 -,
-CH
2
CH
2
CH(CH
3
)CH
2
CH
2 -, -CH 2
CH
2
CH
2
CH(CH
3
)CH
2 -, -CH 2
CH
2
CH
2
CH
2
CH(CH
3 )-, 25 -CH(CH 3
)CH
2
CH
2
CH
2
CH(CH
3 )-;
-CH(CH
2
CH
3
)CH
2
CH
2
CH
2 -, -CH 2
CH(CH
2 CH3)CH 2
CH
2 -,
-CH
2
CH
2
CH(CH
2
CH
3
)CH
2 -, -CH 2 H2CH 2
CH(CH
2
CH
3 )-;
-CH(CH
2
CH
3
)CH
2
CH
2
CH
2
CH
2 -, -CH 2
CH(CH
2
CH
3
)CH
2
CH
2
CH
2 -, 30 -CH 2
CH
2
CH(CH
2
CH
3
)CH
2
CH
2 -, -H2CH 2
CH
2
CH(CH
2
CH
3
)CH
2 -,
-CH
2
CH
2
CH
2
CH
2
CH(CH
2
CH
3 )-;
-CH=CHCH
2
CH
2 -, -CH 2
CH=CHCH
2 -, -CH 2 CH2CH=CH-;
-CH=CHCH
2
CH
2
CH
2 -, -CH 2
CH=CHCH
2
CH
2 -, -CH 2 CH2CH=CHCH 2 -, 35 -CH 2
CH
2
CH
2
CH=CH-;
WO 03/082288 PCT/GB03101463 - 45 -CH=CHCH 2
CHCH
2
CH
2 -, -. CH 2
CH=CHCH
2
CH
2
CH
2 -, -CH 2
CH
2
CH=CHCH
2
CH
2 -,
-CH
2
CH
2
CH
2
CH=CHCH
2 -, -CH 2
CH
2
CH
2
CH
2 CH=CH-; -CH=CHCH=CH-; 5 -CH=CHCH=CHCH 2 -, -CH 2 CH=CHCH=CH-, -CH=CHCH 2 CH=CH-;
-CH=CHCH=CHCH
2
CH
2 -, -CH=CHCH 2
CH=CHCH
2 -, -CH=CHCH 2
CH
2 CH=CH-,
-CH
2
CH=CHCH=CHCH
2 -, -CH 2
CH=CHCH
2 CH=CH-, -CH 2
CH
2 CH=CHCH=CH-;
-C(CH
3 )=CHCH=CH-, -CH=C(CH 3 )CH=CH-, -CH=CHC(CH 3 )=CH-, 10 -CH=CHCH=C(CH 3 )-;
-C=-CCH
2
CH
2 -, -CH 2
C=CCH
2 -, -CH 2
CH
2 C=C-;
-C=-CCH(CH
3
)CH
2 -, -C=-CCH 2
CH(CH
3 )-;
-CH(CH
3
)C=ECCH
2 -, -CH 2
C=CCH(CH
3 )-; 15 -CH(CH 3
)CH
2 C=C-, -CH 2
CH(CH
3 )C=C-; -C=-CCH=CH-, -CH=CHC=-C-, -C=-CC=-C-;
-C=ECCH
2
CH
2
CH
2 -, -CH 2
CH
2
CH
2 C=C-;
-C=CCH
2
CH
2
CH
2
CH
2 -, -CH 2
CH
2
CH
2
CH
2 C=C-; -C=ECCH=CHCH=CH-, -CH=CHC=-C-CH=CH-, -CH=CHCH=CHC=EC-; 20
-C(CH
3 )=CHC=-C-, -CH=C(CH 3 )C=C-, -C=CC(CHg)=CH-, -C=CCH=C(CH 3 )-; cyclopentylene cyclopentenylene; cyclohexylene, cyclohexenylene, cyclohexadienylene; 25 (cyclohex-1 ,4-ylene) (2-cyclohexen-1 ,4-ylene) (2,5-cyclohexadien-I ,4-ylene) (cyclohex-1 ,4-ylene-methylene) (methylene-cyclohex-1 ,4-ylene) WO 03/082288 PCT/GB03/01463 -46 In one preferred embodiment, Q 2 is independently selected from:
-(CH
2
)
5 -;
-(CH
2
)
6 -; 5 -(CH2)7-;
-(CH
2
)
8 -;
-CH(CH
3
)CH
2
CH
2
CH
2
CH
2 -;
-CH
2
CH
2 CH2CH2CH(CH 3 )-;
-CH
2
CH
2
CH(CH
3
)CH
2
CH
2 -; 10 -CH(CH 3
)CH
2
CH
2
CH
2
CH(CH
3 )-;
-CH
2
CH
2
CH
2 CH=CH-;
-CH
2
CH
2
H
2
CH
2 2CH=CH-; and 15 In one preferred embodiment, Q 2 is independently selected from:
-(CH
2
)
5 -;
-(CH
2
)
6 -; -(CH2)7-; 20 -(CH 2
)
8 -;
-CH(CH
3
)CH
2
CH
2 CH2CH 2 -;
-CH
2
CH
2
CH
2
CH
2
CH(CH
3 )-;
-CH
2
CH
2
CH
2 CH=CH-; and,
-CH
2
CH
2
CH
2
H
2 CH=CH-. 25 In one preferred embodiment, Q 2 is independently selected from:
-(CH
2
)
5 -, -(CH 2
)
6 -, -(CH 2
)
7 -, and -(CH 2
)
8 -. The Acid Leader Group, Q 2 : Arylene 30 In one embodiment, the acid leader group, Q 2 , is independently: C5- 20 arylene (denoted -Ar-), and is optionally substituted, WO 03/082288 PCT/GB03/01463 -47 and has a backbone length of at least 4 atoms. In one embodiment, Q 2 is C5- 20 arylene; and is optionally substituted. In one embodiment, Q 2 is Cs- 6 arylene; and is optionally substituted. 5 In one embodiment, Q 2 is phenylene; and is optionally substituted. In one embodiment, Q 2 additionally has a backbone length as described above under the heading "The Acid Leader Group, Q 2 : Backbone Length." 10 The Acid Leader Group, Q 2 : Alkylene-Arylene, Arylene-Alkylene, and Alkylene-Arylene-Alkylene In one preferred embodiment, the acid leader group, Q 2 , is independently: C5- 20 oarylene-C 1 -7alkylene; 15 C 1
.
7 alkylene-Cs- 2 0 arylene; or,
C
1
.
7 alkylene-C 5
-
20 arylene-C 1
.
7 alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms. 20 In one preferred embodiment, the acid leader group, Q 2 , is independently:
C
5
.
20 oarylene-C 1 -7alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms. 25 In one preferred embodiment, the acid leader group, Q 2 , is independently: C4.
7 alkylene-C5- 20 oarylene; or, and is optionally substituted; and has a backbone length of at least 4 atoms. 30 In one preferred embodiment, the acid leader group, Q 2 , is independently:
C
1 l 7 alkylene-C5- 20 arylene-Cl 7 alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms. 35 In one preferred embodiment, Q 2 is independently:
C
5
.
6 arylene-C 1
.
7 alkylene; WO 03/082288 PCT/GB03/01463 -48
C
1 l 7 alkylene-Co- 6 arylene; or,
C
1 l 7 alkylene-Cs 6 arylene-C,_ 7 alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms. 5 In one preferred embodiment, Q 2 is independently: phenylene-C 1
-
7 alkylene; C.l 7 alkylene-phenylene; or,
CI.
7 alkylene-phenylene-C.
7 alkylene; 10 and is optionally substituted; and has a backbone length of at least 4 atoms. In one embodiment, Q 2 is C 1
.
7 alkylene-C5- 20 arylene; and is optionally substituted. In one embodiment, Q 2 is C.-7alkylene-C5- 6 arylene; and is optionally substituted. 15 In one embodiment, Q 2 is independently C 1 7 alkylene-phenylene; and is optionally substituted. In one embodiment, Q 2 is C5- 20 arylene-C 1 -7alkylene; and is optionally substituted. In one embodiment, Q 2 is Cs.
6 arylene-C 1
.
7 alkylene; and is optionally substituted. 20 In one embodiment, Q 2 is independently phenylene-C.
7 alkylene; and is optionally substituted. In one embodiment, Q 2 is Cl- 7 alkylene-C5- 20 arylene-Cl-7alkylene; and is optionally substituted. 25 In one embodiment, Q 2 is C 1 -7alkylene-C 5
.
6 arylene-C 1
.
7 alkylene; and is optionally substituted. In one embodiment, Q 2 is independently C 1
-
7 alkylene-phenylene-C 1
.
7 alkylene; and is optionally substituted. 30 In the above arylene-alkylene (denoted -Ar-RQ 22 -), alkylene-arylene (denoted -RQ2 1 -Ar-), and alkylene-arylene-alkylene (denoted -RQ 2 1 -Ar-R Q22 ) groups,. each of R 2 ' and R Q2 2 is independently Cl.
7 alkylene. In one embodiment, in the above arylene-alkylene, alkylene-arylene, and 35 alkylene-arylene-alkylene groups, each alkylene group is independently: (a) a saturated C 1
.
7 alkylene group; or: WO 03/082288 PCT/GB03/01463 -49 (b) a partially unsaturated C 2
-
7 alkylene group; or: (c) an aliphatic C 1 l 7 alkylene group; or: (d) a linear Cs.
7 alkylene group; or: (e) a branched C2_ 7 alkylene group; or: 5 (f) a saturated aliphatic C 1
.
7 alkylene group; or: (g) a saturated linear C 1
.
7 alkylene group; or: (h) a saturated branched C 2 -7alkylene group; or: (i) a partially unsaturated aliphatic C 2 -7alkylene group; or: (j) a partially unsaturated linear C 2
_
7 alkylene group; or: 10 (k) a partially unsaturated branched C 2
-
7 alkylene group; and is optionally substituted. In one embodiment, Q 2 additionally has a backbone length as described above under the heading "The Acid Leader Group, Q 2 : Backbone Length." 15 Alkylene Groups R Q 2 1 and RQ 22 : Certain Embodiments Note that, for embodiments excluding, e.g., certain backbone lengths, absence of adjacent carbon-carbon double bonds, etc., it is to be understood that the corresponding 20 species listed below are similarly excluded from the respective embodiments discussed below. In one embodiment, each of R Q2 1 and R 22 is independently as defined for Q 1 under the heading "The Cyclyl Leader Group, Q': Alkylene: Certain Embodiments." 25 In one embodiment, R Q2 1 is independently selected from:
-CH
2 -, -(CH 2
)
2 -, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2
)
5 -, -(CH 2
)
6 -,
-CH
2 -CH=CH-; and,
-CH
2 -CH=CH-CH=CH-. 30 In one embodiment, R Q21 is independently selected from:
-CH
2 -, -CH 2
CH
2 -, and -CH 2 -CH=CH-. In one embodiment, R Q21 is independently selected from: 35 -CH 2 - and, -CH 2
CH
2
-.
WO 03/082288 PCT/GB03/01463 - 50 In one embodiment, R 21 is independently -CH 2 -. In one embodiment, R 21 is independently -CH 2
CH
2 -. In one embodiment, R Q2 1 is independently -CH 2 -CH=CH-. In one embodiment, R Q2 1 is independently cis -CH 2 -CH=CH-. 5 In one embodiment, R Q21 is independently trans -CH 2 -CH=CH-. In one embodiment, RQ 22 is independently selected from:
-CH
2 -, -(CH 2
)
2 -, -(CH 2
)
3 -, -(CH 2
)
4 -, -(CH 2
)
5 -, -(CH 2
)
6 -; -CH=CH-; 10 -CH 2 -CH=CH-; -CH=CH-CH=CH-; and, -CH2-CH=CH-CH=CH-. In one embodiment, R Q22 is independently selected from: 15 -CH 2 -, -CH 2
CH
2 -, -CH=CH-, and -CH 2 -CH=CH-. In one embodiment, R Q 22 is independently selected from:
-CH
2 -, -CH 2
CH
2 -, and -CH=CH-. 20 The Acid Leader Group, Q 2 : Certain Phenvlene-Containing Embodiments In one embodiment, Q 2 is independently: phenylene; and is optionally substituted; 25 and has a backbone length of at least 4 atoms. In one embodiment, Q 2 is independently: methylene-phenylene; ethylene-phenylene; 30 and is optionally substituted; and has a backbone length of at least 4 atoms. In one embodiment, Q 2 is independently: phenylene-methylene; 35 phenylene-ethylene; or, phenylene-ethenylene (also known as phenylene-vinylene); WO 03/082288 PCT/GB03/01463 -51 and is optionally substituted; and has a backbone length of at least 4 atoms. In one embodiment, Q 2 is independently: 5 methylene-phenylene-methylene; methylene-phenylene-ethylene; methylene-phenylene-ethenylene; 10 ethylene-phenylene-methylene; ethylene-phenylene-ethylene; ethylene-phenylene-ethenylene; and is optionally substituted; 15 and has a backbone length of at least 4 atoms. In the above phenylene, phenylene-alkylene, alkylene-phenylene, and alkylene-phenylene-alkylene groups, the phenylene linkage may be ortho (i.e., 1,2-), meta (i.e., 1,3-), or para (i.e., 1,4-), and the phenylene group is optionally substituted with from 20 1 to 4 substituents, RB: RB RR R ortho meta para In one embodiment, the phenylene linkage is meta or para. In one embodiment, the phenylene linkage is meta. 25 In one embodiment, the phenylene linkage is para. In one embodiment, m is an integer from 0 to 4. In one embodiment, m is an integer from 0 to 3. In one embodiment, m is an integer from 0 to 2. 30 In one embodiment, m is 0 or 1. In one embodiment, m is an integer from 1 to 4. In one embodiment, m is an integer from 1 to 3.
WO 03/082288 PCT/GB03/01463 - 52 In one embodiment, m is 1 or 2. In one embodiment, m is 4. In one embodiment, m is 3. In one embodiment, m is 2. 5 In one embodiment, m is 1. In one embodiment, m is 0. In one embodiment, the phenylene group is unsubstituted. In one embodiment, the phenylene group is optionally substituted. 10 In one embodiment, the phenylene group is substituted. Examples of substituents, RB, include, but are not limited to, those described under the heading "Substituents" below. 15 In one embodiment, the substituents , RB, are as defined under the heading "The Cyclyl Group, Cy: Optionally Substituted Phenyl: Substituents." Examples of preferred substituents, R3, include, but are not limited to, the following: fluoro, chloro, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, 20 isopropoxy, methylthio, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro, and phenyl. In one embodiment, the compounds have the following formula, in which Q 2 is para arylene: B Rm 2 Cy-Q- J-N 1 4 N-J 0 (9) II C-N-OH p H 25 In one embodiment, the compounds have the following formula, in which Q 2 is alkylene meta/para-arylene: B R M 1 1 2 Q21 Cy-Q- J-NI 4N-J-R I (10) C-N-OH H m or p WO 03/082288 PCT/GB03/01463 - 53 In one embodiment, the compounds have the following formula, in which Q 2 is arylene meta/para-alkylene: RB 1 1, 2 Cy-Q J N1 4N-J O (11) Q 22 .. R C-N-OH H m or p In one embodiment, the compounds have the following formula, in which Q 2 is alkylene 5 arylene-meta/para-alkylene: RB 1 12 Q21 Cy-Q J-N 1 4N-J- R O (12) Q22 11 R -- N---OH H m or p In one embodiment, Q 2 has the following formula (referred to herein as "para-phenylene"): RB 10 In one embodiment, Q 2 has the following formula (referred to herein as "methylene meta/para-phenylene"): B R m mor p In one embodiment, Q 2 has the following formula (referred to herein as "methylene 15 meta-phenylene"):
RB
WO 03/082288 PCT/GB03/01463 - 54 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted methylene-meta-phenylene"): 5 In one embodiment, Q 2 has the following formula (referred to herein as "ethylene-meta/para-phenylene"):
R
B morp In one embodiment, Q 2 has the following formula (referred to herein as 10 "ethylene-meta-phenylene"): B R m In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted ethylene-meta-phenylene"): 15 In one embodiment, Q 2 has the following formula (referred to herein as "phenylene meta/para-methylene"): RB m orp 20 WO 03/082288 PCT/GB03/01463 2 55 In one embodiment, Q 2 has the following formula (referred to herein as "phenylene-meta methylene"): RD 5 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted phenylene-meta-methylene"): In one embodiment, Q 2 has the following formula (referred to herein as "methylene 10 phenylene-metalpara-methylene"): RB morp In one embodiment, Q 2 has the following formula (referred to herein as "methylene phenylene-meta-methylene"): B R m 15 I 1 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted methylene-phenylene-meta-methylene"): 20 WO 03/082288 PCT/GB03/01463 - 56 In one embodiment, Q 2 has the following formula (referred to herein as "ethylene-phenylene-meta/para-methylene"): RB m orp 5 In one embodiment, Q 2 has the following formula (referred to herein as "ethylene-phenylene-meta-methylene"):
R
B In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted 10 ethylene-phenylene-meta-methylene"): In one embodiment, Q 2 has the following formula (referred to herein as "phenylene meta/para-trans-ethenylene"): RB 15 m or p 15 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted phenylene-metalpara-trans-ethenylene"): m orp 20 WO 03/082288 PCT/GB03/01463 - 57 In one embodiment, Q 2 has the following formula (referred to herein as "phenylene-meta trans-ethenylene"): RB 5 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted phenylene-meta-trans-ethenylene"): In one embodiment, Q 2 has the following formula (referred to herein as "phenylene 10 meta/para-ethylene"): R m orp In one embodiment, Q 2 has the following formula (referred to herein as "phenylene-meta ethylene"): RB 15 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted phenylene-meta-ethylene"): 20 WO 03/082288 PCT/GB03/01463 - 58 In one embodiment, Q 2 has the following formula (referred to herein as "methylene phenylene-meta/para-trans-ethenylene"): RB morp 5 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted methylene-phenylene-meta/para-trans-ethenylene"): m or p In one embodiment, Q 2 has the following formula (referred to herein as "methylene 10 phenylene-meta-trans-ethenylene"): B Rm In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted methylene-phenylene-meta-trans-ethenylene"): 15 In one embodiment, Q 2 has the following formula (referred to herein as "methylene phenylene-meta/para-ethylene"): BM Rm m orp 20 WO 03/082288 PCT/GB03/01463 -59 In one embodiment, Q 2 has the following formula (referred to herein as "methylene phenylene-meta-ethylene"): RB 5 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted methylene-phenylene-meta-ethylene"): In one embodiment, Q 2 has the following formula (referred to herein as 10 "ethylene-phenylene-meta/para-trans-ethenylene"):
R
a M morp In one embodiment, Q 2 has the following formula (referred to herein as "ethylene-phenylene-meta-trans-ethenylene"): RB 15 In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted ethylene-phenylene-meta-trans-ethenylene"): 20 WO 03/082288 PCT/GB03/01463 - 60 In one embodiment, Q 2 has the following formula (referred to herein as "ethylene-phenylene-meta/para-ethylene"): B m or p 5 In one embodiment, Q 2 has the following formula (referred to herein as "ethylene-phenylene-meta-ethylene"): B In one embodiment, Q 2 has the following formula (referred to herein as "unsubstituted 10 ethylene-phenylene-meta-ethylene"): In one embodiment, Q 2 additionally has a backbone length as described above under the heading "The Acid Leader Group, Q 2 : Backbone Length." 15 WO 03/082288 PCT/GB03/01463 - 61 Examples of Specific Embodiments Some individual embodiments of the present invention include the following compounds. N O0 PX117402 1,. 'C N,OH (Ex 140) 11 H 0 O.OH 0 O r''N N 0H"N J H PX117403 2. (Ex 141) o 0 II I ,C , /- .OH N N OPX117404 3 H 3. NJ (Ex 142) PX1 17764 4N 0 (Ex 143) NC NOH II H 0 N 0 PX117768 .OMe N'. NOH (Ex 144) OMe 0 U II H 0 0 T N OH PX118490 6. & N \,N-S - . N.( x4 - _./ II / j OH (Ex 40) 0 0 WO 03/082288 PCT/GB03/01463 -62 00 PX118491 II H (Ex 41) 00 Cl 8N PX118791 N"'C NOH (Ex 145) II H 0 0 0 111 .O Cl N OPX1 18792 9N(Ex 146) 11 H Cl 0 \1 I-\ I I II H PXl 18807 12. " -- N \ N-S--_ ; ; ,N., O
CN
/ -- I I v "-OH(Ex 45) S00 OMe / -PX118793 10. 0 1. N (Ex 147) CI O 0 H PX118794 11. (Ex 148) CI O /\ II H PX118807 12.N N-S Ns. .~ O (x5 N - 0 H(E 5 O -sO 13I 'H PX118810 13. N N-S OHE42 WO 03/082288 PCT/GB03/01463 - 63 00 14. , N \ N-- OH (Ex 43) 15. N- N- 'O P118 0 0 O O 0 00 0 1-- N' O PX118830 16. NOH (Ex 149) II H O O 0 0 ' N 0 PX118831 17. .... c N OH (Ex 150) II H O 0 SN O PX118832 18. Me.. . N NO H (Ex 151) I II H Me O O 0 r\- N 0O PX118844 19. NC,/ N.'C ' NH (Ex 163) II H O O O II I COH Nv " NPX118845 20 H 20. N (Ex 164) IN MeO 21.N O PX118846 21.'o NOH (Ex 152) II H
O
WO 03/082288 PCT/GB03/01463 -64 22. MeO N PX118847 2"2'O - H (Ex 153) II H O Me I PX118848 23. 'N -- N ' - 0 NC NO H (Ex 165) II H 0 0 2 N",. O N 24.N O PX118849 24. C NOH (Ex 154) II H 0 N 25. N N 0 PX118850 25. NH (Ex 166) II H 0 H N N'OH PX118859 26. F N 0O (Ex 174) O H N NN
'
OH PX118860 27., N O (Ex 175) 28L~. - H PX118870 28. N. N N-S N - NOH(E52 00 O 11 \ N - H PX 18871 29. MeO - N \ N-S]PX15 N1OH 0 WO 03/082288 PCT/GB03/01463 -65 S H PX118872 30. N \ N -S *][N - NO (E54 I I O 0 0 (Ex 54) MeO 31. N N ' HX~15 o 0' o 011 H PX118874 31. N N-S NH O OH (Ex 56) / 0 I H PX118874 3. N N-S--- N.. 323. N 1 II OH (Ex57) F 34 . OH PX 118876 33. -N \ N-S--.. .> . A -N Me Me0 35.0 OH PXE18877 0OH (Ex 57) II0 F I H PX118876 34. N N- N 06. OH (Ex 58) Me Me NH L NSH PXl 18877 35. N - 0 NOH (Ex 72) o 0 F 0 \-/II I H PX1 18882 NN -aO (Ex 72) 0 \ /7 H 2 P0 3
-
0 0 WO 03/082288 PCT/GB03101463 -66 /\ N N-S 38. - .... H. PX118891 F8 N , OH (Ex 74) 0 /\ N N -S H- PX1 18892 39.O N .OH (Ex 75) 0 / 1/ i H PX1 18893 40. N \ N- N*. - ~ 1 OH (xl 0 0 O2N /N. -\ H PX1 18894 41. / \N'' N OH C:0 N0O (Ex 62) N 0 0 F PX1 18898 42. N 0(Ex 176) 11 H Me 4.Me a N 0 PX1 18899 II H H SN 44. / ' 0 PXI 18900 (Ex 178) I I H WO 03/082288 PCT/GB03/01463 - 67 0 I I
O,
° , , \ CN O PX118901 45. 45/ ,0 OH (Ex 179) II H O Me HON ' 46 N oPX118903 47. ON .0H (Ex 181) II H 0 O N, OH PXI 18904 48. H (Ex 182) O 11 H 0 ---.- N 0 S -- ¢/ "1 49 . e'H PX1 18905 9 OH (Ex 76) O O 50. C '- OH X~ 9 9 I H PX118908 OC e 0 '"-' "" N"{ 1 / O (Ex 76) 0 0 N N-S -x 190 50.-I H P180 02. C NH (Ex 77) 0 N 0 51. N PX1890 O ~ . N 0 (Ex 78) 0 52. - 1 1 N 0 PX1 18908 5.N, C"N OH (Ex 183) 11 H
O
WO 03/082288 PCT/GB03/01463 - 68 3 N 0 PX118909 53. "N'"" C N"OH (Ex 184) 11 H O CO 0 -- II PX118910 54. N N-S o4. N- OH (Ex 79) OH o IIH S -N N-S x1891 55. 11 H Me Me H (Ex 80) 0 Me Me I II 56. II OH 0 o (Ex 63) I OH (Ex 64) 0 0 10 58. 0I H PX118918 o OH (Ex 73) 0 0 H MeO N N OH PX118927 59. \N 0 5(Ex 155) 59. N
H
WO 03/082288 PCT/GB03/01463 - 69 Me I M e N " 60. MeN O PX118928 N
N
O H (Ex 167) O 0 0 H 61. . O 'H xj1 'N - N 0 (Ex 168) 0 0 H 62. N "OH PX118930 N N O (Ex 156) 0 H 63. N OH PX1 18931 63O N 0 (Ex 157) Me- 0 0 H 64. OH PX 18932 64. N COOH (Ex 158) N COOH H H2C 0 -" H PX118933 N N-(S .. N6) 65. Hl ' 14
"
OH XE1463 00 OO 66. 0 PX118934 66. I I H N N-S N (Ex 48) 0 OH 00 00 60
O
WO 03/082288 PCT/GB03/01463 -70 CF N N -S-OH Ex 70 68. I II H PX118937 O Me 2 N-. 69. MeH PX118951 S1 H (Ex47) 0 0 F SI PX118965 70 N N- N'H (Ex 71) 70. N N-S-- 'k _ / II j I H E 1 0 0. N.. 0E H OH F O H N N.OH PX118967 71. N 0 (Ex 159) 0 72. H PX118968 72.H N N N,.(E NNOH (Ex 169) O O 0 73. N H PX118969 N N NOH (Ex 170) H OH O O 74. N H PX118970 NN N H 'OH (Ex 171) O O CI O O 75.1 PX118971 NI N- N. .N H (Ex 50) 00 WO 03/082288 PCT/GB03/01463 -71 O O 7.cN \ N-S 1! N,O 76.CI - I O (Ex 51) 00 77. H PX1 18978 N N NOH (Ex 172) O O Cl C l PX118989 78. N H (Ex 160) N N Y - N, OH O 0 F 79. H PX118990 N NOH (Ex 161) O O Cl 80N H PX118991 N NOH (Ex 162) 1 H O O Me Me 81. PX118994 81.N SH (Ex 173) N NN'OH O O 82. N N-SH II OH 0I 0 WO 03/082288 PCT/GB03/01463 - 72 H -~N 83. H N N-S-. .. N v - OH o 0 0 II N N-S 84. H vi H 0 0 0o 86. v N N-S 85. 11H O N OH 0 OH 0 87. N N-S OI H N, OH 0 88. N N-S H 89. e c N H 0 0 NN'H 90. C N O OH 0 WO 03/082288 PCT/GB03/01463 - 73 91. O O ,Tx/V N OH o 0 11 91. N NOH O O H N J 94. ,Oq. ..t H 0 0 11 95 11 NOH II H O 96. NJO NN OH H 0 0 97. N, , N0 II H 0 95. N O N, OH H 0 97.0 II H 98. 0 N N 0 H II H 0 WO 03/082288 PCT/GB03/01463 -74 S N 0 99. C '.,O II H O 0N 100.
-
N C N H N 0 .OH, H II H 0 Note that, where the above examples are salts (e.g., PX118932, PX1 18882), other analogous salts may also be prepared. 5 Chemical Terms The term "carbo," "carbyl," "hydrocarbo," and "hydrocarbyl," as used herein, pertain to compounds and/or groups which have only carbon and hydrogen atoms (but see "carbocyclic" below). 10 The term "hetero," as used herein, pertains to compounds and/or groups which have at least one heteroatom, for example, multivalent heteroatoms (which are also suitable as ring heteroatoms) such as boron, silicon, nitrogen, phosphorus, oxygen, sulfur, and selenium (more commonly nitrogen, oxygen, and sulfur) and monovalent heteroatoms, 15 such as fluorine, chlorine, bromine, and iodine. The term "saturated," as used herein, pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds. 20 The term "unsaturated," as used herein, pertains to compounds and/or groups which have at least one carbon-carbon double bond or carbon-carbon triple bond. The term "aliphatic," as used herein, pertains to compounds and/or groups which are linear or branched, but not cyclic (also known as "acyclic" or "open-chain" groups). 25 The term "ring," as used herein, pertains to a closed ring of from 3 to 10 covalently linked atoms, more preferably 3 to 8 covalently linked atoms, yet more preferably 5 to 6 covalently linked atoms. A ring may be an alicyclic ring or an aromatic ring. The term "alicyclic ring," as used herein, pertains to a ring which is not an aromatic ring.
WO 03/082288 PCT/GB03/01463 - 75 The term "carbocyclic ring," as used herein, pertains to a ring wherein all of the ring atoms are carbon atoms. 5 The term "carboaromatic ring," as used herein, pertains to an aromatic ring wherein all of the ring atoms are carbon atoms. The term "heterocyclic ring," as used herein, pertains to a ring wherein at least one of the ring atoms is a multivalent ring heteroatom, for example, nitrogen, phosphorus, silicon, 10 oxygen, or sulfur, though more commonly nitrogen, oxygen, or sulfur. Preferably, the heterocyclic ring has from 1 to 4 heteroatoms. The term "cyclic compound," as used herein, pertains to a compound which has at least one ring. The term "cyclyl," as used herein, pertains to a monovalent moiety obtained by 15 removing a hydrogen atom from a ring atom of a cyclic compound. Where a cyclic compound has two or more rings, they may be fused (e.g., as in naphthalene), bridged (e.g., as in norbornane), spiro (e.g., as in spiro[3.3]heptane), or a combination thereof. Cyclic compounds with one ring may be referred to as "monocyclic" 20 or "mononuclear," whereas cyclic compounds with two or more rings may be referred to as "polycyclic" or "polynuclear." The term "carbocyclic compound," as used herein, pertains to a cyclic compound which has only carbocyclic ring(s). 25 The term "heterocyclic compound," as used herein, pertains to a cyclic compound which has at least one heterocyclic ring. The term "aromatic compound," as used herein, pertains to a cyclic compound which has 30 at least one aromatic ring. The term "carboaromatic compound," as used herein, pertains to a cyclic compound which has only carboaromatic ring(s). 35 The term "heteroaromatic compound," as used herein, pertains to a cyclic compound which has at least one heteroaromatic ring.
WO 03/082288 PCT/GB03/01463 -76 The term "monodentate substituents," as used herein, pertains to substituents which have one point of covalent attachment. 5 The term "monovalent monodentate substituents," as used herein, pertains to substituents which have one point of covalent attachment, via a single bond. Examples of such substituents include halo, hydroxy, and alkyl. The term "multivalent monodentate substituents," as used herein, pertains to substituents 10 which have one point of covalent attachment, but through a double bond or triple bond. Examples of such substituents include oxo, imino, alkylidene, and alklidyne. The term "bidentate substituents," as used herein, pertains to substituents which have two points of covalent attachment, and which act as a linking group between two other 15 moieties. Examples of such substituents include alkylene and arylene. Substituents The phrase "optionally substituted," as used herein, pertains to a parent group which may 20 be unsubstituted or which may be substituted. Unless otherwise specified, the term "substituted," as used herein, pertains to a parent group which bears one or more substituents. The term "substituent" is used herein in the conventional sense and refers to a chemical moiety which is covalently attached to, 25 appended to, or if appropriate, fused to, a parent group. A wide variety of substituents are well known, and methods for their formation and introduction into a variety of parent groups are also well known. The substituents are described in more detail below. 30 Alkyl: The term "alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated. Thus, the term "alkyl" 35 includes the sub-classes alkenyl, alkynyl, cycloalkyl, etc., discussed below.
WO 03/082288 PCT/GB03/01463 -77 In this context, the prefixes (e.g., C14, C1-7, C1-20, C2- 7 , C 3
.-
7 , etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "C 1 4 alkyl," as used herein, pertains to an alkyl group having from 1 to 4 carbon atoms. Examples of groups of alkyl groups include C 1
.
4 alkyl ("lower alkyl"), C 1
.
7 alkyl, and C1- 20 alkyl. 5 Examples of (unsubstituted) saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2), propyl (C3), butyl (C4), pentyl (C5), hexyl (C 6 ), heptyl (07), octyl (C8), nonyl (Cq), decyl (CIo), undecyl (C 11 ), dodecyl (C 1 2 ), tridecyl (C 1 3 ), tetradecyl (C 14 ), pentadecyl (C15), and eicodecyl (C20). 10 Examples of (unsubstituted) saturated linear alkyl groups include, but are not limited to, methyl (CI), ethyl (C2), n-propyl (C 3 ), n-butyl (C 4 ), n-pentyl (amyl) (C5), n-hexyl (Ce), and n-heptyl (07). 15 Examples of (unsubstituted) saturated branched alkyl groups include iso-propyl (C3), iso-butyl (C4), sec-butyl (C4), tert-butyl (C4), iso-pentyl (C5), and neo-pentyl (C5). Cycloalkyl: The term "cycloalkyl," as used herein, pertains to an alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from 20 an alicyclic ring atom of a cyclic hydrocarbon (carbocyclic) compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 3 to 7 ring atoms. Examples of (unsubstituted) saturated cylcoalkyl groups include, but are not limited to, 25 those derived from: cyclopropane (C3), cyclobutane (C4), cyclopentane (C5), cyclohexane (Ce), cycloheptane (C7), norbornane (07), norpinane (07), norcarane (07), adamantane (C10), and decalin (decahydronaphthalene) (CIo). Examples of (substituted) saturated cycloalkyl groups, which are also referred to herein 30 as "alkyl-cycloalkyl" groups, include, but are not limited to, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, and dimethylcyclohexyl, menthane, thujane, carane, pinane, bornane, norcarane, and camphene. 35 Examples of (substituted) unsaturated cyclic alkenyl groups, which are also referred to herein as "alkyl-cycloalkenyl" groups, include, but are not limited to, methylcyclopropenyl, WO 03/082288 PCT/GB03/01463 -78 dimethylcyclopropenyl, methylcyclobutenyl, dimethylcyclobutenyl, methylcyclopentenyl, dimethylcyclopentenyl, methylcyclohexenyl, and dimethylcyclohexenyl. Examples of (substituted) cycloalkyl groups, with one or more other rings fused to the 5 parent cycloalkyl group, include, but are not limited to, those derived from: indene (C 9 ), indan (e.g., 2,3-dihydro-1 H-indene) (C), tetraline (1,2,3,4-tetrahydronaphthalene (Co10), acenaphthene (C 12 ), fluorene (C 13 ), phenalene (C13), acephenanthrene (C 1 5), aceanthrene (C16). For example, 2H-inden-2-yl is a Cecycloalkyl group with a substituent (phenyl) fused thereto. 10 Alkenyl: The term "alkenyl," as used herein, pertains to an alkyl group having one or more carbon-carbon double bonds. Examples of groups of alkenyl groups include
C
24 alkenyl, C 2 -7alkenyl, C 2
-
20 alkenyl. 15 Examples of (unsubstituted) unsaturated alkenyl groups include, but are not limited to, ethenyl (vinyl, -CH=CH 2 ), 1-propenyl (-CH=CH-CH 3 ), 2-propenyl (allyl, -CH-CH=CH 2 ), isopropenyl (-C(CH 3
)=CH
2 ), butenyl (C4), pentenyl (C 5 ), and hexenyl (Ce). Examples of (unsubstituted) unsaturated cyclic alkenyl groups, which are also referred to 20 herein as "cycloalkenyl" groups, include, but are not limited to, cyclopropenyl (C03), cyclobutenyl (C4), cyclopentenyl (C5), and cyclohexenyl (Ce). Alkynyl: The term "alkynyl," as used herein, pertains to an alkyl group having one or more carbon-carbon triple bonds. Examples of groups of alkynyl groups include C 2 4alkynyl, 25 C 2
.
7 alkynyl, C 2
-
20 alkynyl. Examples of (unsubstituted) unsaturated alkynyl groups include, but are not limited to, ethynyl (ethinyl, -C=CH) and 2-propynyl (propargyl, -CH 2 -C=CH). 30 Alkylidene: The term "alkylidene," as used herein, pertains to a divalent monodentate moiety obtained by removing two hydrogen atoms from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated. Examples of groups of alkylidene groups include 35 C 1
-
4 alkylidene, C 1 7 alkylidene, C 1 -20alkylidene.
WO 03/082288 PCT/GB03/01463 - 79 Examples of alkylidene groups include, but are not limited to, methylidene (=CH 2 ), ethylidene (=CH-CH 3 ), vinylidene (=C=CH 2 ), and isopropylidene (=C(CH 3
)
2 ). An example of a substituted alkylidene is benzylidene (=CH-Ph). 5 Alkylidyne: The term "alkylidyne," as used herein, pertains to a trivalent monodentate moiety obtained by removing three hydrogen atoms from a carbon atom of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, or a combination thereof, and which may be saturated, partially unsaturated, or fully unsaturated. Examples of groups of alkylidyne groups include 10 C 1 4alkylidyne, C1.
7 alkylidyne, C 1
-
20 alkylidyne. Examples of alkylidyne groups include, but are not limited to, methylidyne (=CH) and ethylidyne (=C-CH 3 ). 15 Carbocyclyl: The term "carbocyclyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring atom of a carbocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 3 to 7 ring atoms. 20 In this context, the prefixes (e.g., C3-2o, C3.7, C5.6, etc.) denote the number of ring atoms, or range of number of ring atoms. For example, the term "Ce- 6 carbocyclyl," as used herein, pertains to a carbocyclyl group having 5 or 6 ring atoms. Examples of groups of carbocyclyl groups include C 3
-
20 carbocyclyl, C3-10carbocyclyl, C- 1 locarbocyclyl,
C
3
.
7 carbocyclyl, and C5.7carbocyclyl. 25 Examples of carbocyclic groups include, but are not limited to, those described above as cycloalkyl groups; and those described below as carboaryl groups. Heterocyclyl: The term "heterocyclyl," as used herein, pertains to a monovalent moiety 30 obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. 35 In this context, the prefixes (e.g., C3.20, C3- 7 , C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the WO 03/082288 PCT/GB03/01463 - 80 term "C5- 6 heterocyclyl," as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms. Examples of groups of heterocyclyl groups include C3- 20 heterocyclyl,
C
3
.
7 heterocyclyl, C5-7heterocyclyl, and C5.
6 heterocyclyl. 5 Examples of (non-aromatic) monocyclic heterocyclyl groups include, but are not limited to, those derived from: NI: aziridine (C3), azetidine (C4), pyrrolidine (tetrahydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), 10 piperidine (C6), dihydropyridine (C 6 ), tetrahydropyridine (C), azepine (C7); O1: oxirane (C3), oxetane (C4), oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran (C 6 ), pyran (C 6 ), oxepin (C7); 15 S 1 : thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5), thiane (tetrahydrothiopyran) (C6), thiepane (C7); 02: dioxolane (C), dioxane (C3), and dioxepane (07); 20 03: trioxane (C6);
N
2 : imidazolidine (C5), pyrazolidine (diazolidine) (C5), imidazoline (C5), pyrazoline (dihydropyrazole) (C5), piperazine (C6); 25 N 1 0 1 : tetrahydrooxazole (C5), dihydrooxazole (C5), tetrahydroisoxazole (Cs), dihydroisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6), dihydrooxazine (C), oxazine (C6);
N
1
S
1 : thiazoline (Cs), thiazolidine (Cs), thiomorpholine (Ce); 30
N
2 0 1 : oxadiazine (C6);
O
1
S
1 : oxathiole (Cs) and oxathiane (thioxane) (CO6); and, 35 N 1 0 1 S: oxathiazine (CE).
WO 03/082288 PCT/GB03/01463 - 81 Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include saccharides, in cyclic form, for example, furanoses (C 5 ), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C 6 ), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, 5 galactopyranose, and talopyranose. Examples of heterocyclyl groups which are also heteroaryl groups are described below with aryl groups. 10 Aryl: The term "aryl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 5 to 7 ring atoms. 15 In this context, the prefixes (e.g., C3-20, C5-7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C 5
-
6 aryl," as used herein, pertains to an aryl group having 5 or 6 ring atoms. Examples of groups of aryl groups include C 3 20 aryl, C 3
.-
12 aryl, C5- 12 aryl, C5-7aryl, and
C
5
-
6 aryl. 20 The ring atoms may be all carbon atoms, as in "carboaryl groups" (e.g., Co.20carboaryl). Examples of carboaryl groups include, but are not limited to, those derived from benzene (i.e., phenyl) (C), naphthalene (C 1 0 ), azulene (Co 10 ), anthracene (C 1 4 ), phenanthrene (C 1 4 ), 25 naphthacene (C 1 8 ), and pyrene (C16). Examples of aryl groups which comprise fused rings, at least one of which is an aromatic ring, include, but are not limited to, groups derived from indene (Ce), isoindene (C 9 ), and fluorene (C13). 30 Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroaryl groups" (e.g., C 5
-
20 heteroaryl). Examples of monocyclic heteroaryl groups include, but are not limited to, those derived 35 from: NI: pyrrole (azole) (C5), pyridine (azine) (C6); WO 03/082288 PCT/GB03/01463 - 82 01: furan (oxole) (C 5 );
S
1 : thiophene (thiole) (C5);
N
1 0 1 : oxazole (C5), isoxazole (C 5 ), isoxazine (C6);
N
2 0 1 : oxadiazole (furazan) (C 5 ); 5 N 3 0 1 : oxatriazole (C5);
N
1 Sj: thiazole (C), isothiazole (C5);
N
2 : imidazole (1,3-diazole) (C5), pyrazole (1,2-diazole) (C5), pyridazine (1,2-diazine) (C), pyrimidine (1,3-diazine) (C) (e.g., cytosine, thymine, uracil), pyrazine (1,4-diazine) (C6);
N
3 : triazole (CS), triazine (Ce); and, 10 N 4 : tetrazole (Cq). Examples of heterocyclic groups (some of which are also heteroaryl groups) which comprise fused rings, include, but are not limited to: Cgheterocyclic groups (with 2 fused rings) derived from benzofuran (01), 15 isobenzofuran (O1), indole (Ni), isoindole (Ni), indolizine (N 1 ), indoline (NI), isoindoline
(N
1 ), purine (N 4 ) (e.g., adenine, guanine), benzimidazole (N 2 ), indazole (N 2 ), benzoxazole
(N
1 0 1 ), benzisoxazole (N 1 0 1 ), benzodioxole (02), benzofurazan (N 2 0 1 ), benzotriazole
(N
3 ), benzothiofuran (Si), benzothiazole (N 1
S
1 ), benzothiadiazole (N 2 S);
C
0 loheterocyclic groups (with 2 fused rings) derived from chromene (01), 20 isochromene (O), chroman (0), isochroman (01), benzodioxan (02), quinoline (N 1 ), isoquinoline (N 1 ), quinolizine (N 1 ), benzoxazine (N 1 0 1 ), benzodiazine (N 2 ), pyridopyridine
(N
2 ), quinoxaline (N 2 ), quinazoline (N 2 ), cinnoline (N 2 ), phthalazine (N 2 ), naphthyridine
(N
2 ), pteridine (N 4 );
C
13 heterocyclic groups (with 3 fused rings) derived from carbazole (Ni), 25 dibenzofuran (O0), dibenzothiophene (S 1 ), carboline (N 2 ), perimidine (N 2 ), pyridoindole
(N
2 ); and,
C
1 4 heterocyclic groups (with 3 fused rings) derived from acridine (N 1 ), xanthene (01), thioxanthene (S 1 ), oxanthrene (02), phenoxathiin (0 1
S
1 ), phenazine (N 2 ), phenoxazine (N 1 0 1 ), phenothiazine (N 1
S
1 ), thianthrene (Sz), phenanthridine (N 1 ), 30 phenanthroline (N 2 ), phenazine (N 2 ). Heterocyclic groups (including heteroaryl groups) which have a nitrogen ring atom in the form of an -NH- group may be N-substituted, that is, as -NR-. For example, pyrrole may be N-methyl substituted, to give N-methypyrrole. Examples of N-substituents include, but 35 are not limited to C 1
.
7 alkyl, C3- 20 heterocyclyl, C- 2 0 aryl, and acyl groups.
WO 03/082288 PCT/GB03/01463 -83 Heterocyclic groups (including heteroaryl groups) which have a nitrogen ring atom in the form of an -N= group may be substituted in the form of an N-oxide, that is, as -N(->O)= (also denoted -N*(---O~)=). For example, quinoline may be substituted to give quinoline N-oxide; pyridine to give pyridine N-oxide; benzofurazan to give benzofurazan N-oxide 5 (also known as benzofuroxan). Cyclic groups may additionally bear one or more oxo (=0) groups on ring carbon atoms. Monocyclic examples of such groups include, but are not limited to, those derived from:
C
5 : cyclopentanone, cyclopentenone, cyclopentadienone; 10 C 6 : cyclohexanone, cyclohexenone, cyclohexadienone; O1: furanone (Cs), pyrone (C 6 );
N
1 : pyrrolidone (pyrrolidinone) (C5), piperidinone (piperidone) (C6), piperidinedione (C 6 ); Nz: imidazolidone (imidazolidinone) (C 5 ), pyrazolone (pyrazolinone) (C 5 ), piperazinone (C6), piperazinedione (C 6 ), pyridazinone (C6), pyrimidinone (C 6 ) (e.g., cytosine), 15 pyrimidinedione (C6) (e.g., thymine, uracil), barbituric acid (C6);
N
1 S: thiazolone (C 6 ), isothiazolone (Cs);
N
1 0O 1 : oxazolinone (C 5 ). Polycyclic examples of such groups include, but are not limited to, those derived from: 20 C 9 : indenedione; CIo: tetralone, decalone;
C
14 : anthrone, phenanthrone;
N
1 : oxindole (C9); O1: benzopyrone (e.g., coumarin, isocoumarin, chromone) (CIo); 25 N 1 0 1 : benzoxazolinone (Ce), benzoxazolinone (Clo);
N
2 : quinazolinedione (CO10);
N
4 : purinone (C 9 ) (e.g., guanine). Still more examples of cyclic groups which bear one or more oxo (=0) groups on ring 30 carbon atoms include, but are not limited to, those derived from: cyclic anhydrides (-C(=O)-O-C(=O0)- in a ring), including but not limited to maleic anhydride (Cs), succinic anhydride (C), and glutaric anhydride (Ce); cyclic carbonates (-O-C(=0)-O- in a ring), such as ethylene carbonate (C5) and 1,2-propylene carbonate (C5); 35 imides (-C(=O)-NR-C(=0)- in a ring), including but not limited to, succinimide (Cs), maleimide (C), phthalimide, and glutarimide (C6); WO 03/082288 PCT/GB03/01463 - 84 lactones (cyclic esters, -O-C(=O)- in a ring), including, but not limited to, P-propiolactone, y-butyrolactone, 5-valerolactone (2-piperidone), and E-caprolactone; lactams (cyclic amides, -NR-C(=O)- in a ring), including, but not limited to, 1-propiolactam (C4), y-butyrolactam (2-pyrrolidone) (C5), 6-valerolactam (C), and 5 E-caprolactam (C 7 ); cyclic carbamates (-O-C(=O)-NR- in a ring), such as 2-oxazolidone (C); cyclic ureas (-NR-C(=O)-NR- in a ring), such as 2-imidazolidone (C5) and pyrimidine-2,4-dione (e.g., thymine, uracil) (C6). 10 The above alkyl, alkylidene, alkylidyne, heterocyclyl, and aryl groups, whether alone or part of another substituent, may themselves optionally be substituted with one or more groups selected from themselves and the additional substituents listed below. Hydrogen: -H. Note that if the substituent at a particular position is hydrogen, it may be 15 convenient to refer to the compound as being "unsubstituted" at that position. Halo: -F, -CI, -Br, and -I. Hydroxy: -OH. 20 Ether: -OR, wherein R is an ether substituent, for example, a CI.
7 alkyl group (also referred to as a C 1
_
7 alkoxy group, discussed below), a C 3
-
20 heterocyclyl group (also referred to as a
C
3
-
20 heterocyclyloxy group), or a C5.
20 aryl group (also referred to as a C5- 20 aryloxy group), preferably a C 1 7 alkyl group. 25
C
1
.
7 alkoxy: -OR, wherein R is a C 1
.
7 alkyl group. Examples of C1.
7 alkoxy groups include, but are not limited to, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), -O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy). 30 Acetal: -CH(OR 1
)(OR
2 ), wherein R 1 and R 2 are independently acetal substituents, for example, a Cs_ 7 alkyl group, a C 3 -20heterocyclyl group, or a C5- 2 0 aryl group, preferably a
C
1
.
7 alkyl group, or, in the case of a "cyclic" acetal group, R 1 and R 2 , taken together with the two oxygen atoms to which they are attached, and the carbon atoms to which they are 35 attached, form a heterocyclic ring having from 4 to 8 ring atoms. Examples of acetal groups include, but are not limited to, -CH(OMe) 2 , -CH(OEt) 2 , and -CH(OMe)(OEt).
WO 03/082288 PCT/GB03/01463 - 85 Hemiacetal: -CH(OH)(OR 1 ), wherein R 1 is a hemiacetal substituent, for example, a
C
1
.
7 alkyl group, a C 3
-
20 heterocyclyl group, or a Cs- 20 aryl group, preferably a Cl_ 7 alkyl group. Examples of hemiacetal groups include, but are not limited to, -CH(OH)(OMe) and 5 -CH(OH)(OEt). Ketal: -CR(OR 1
)(OR
2 ), where R 1 and R 2 are as defined for acetals, and R is a ketal substituent other than hydrogen, for example, a C 1 7 alkyl group, a C 3
-
2 0 heterocyclyl group, or a Cs-.
20 aryl group, preferably a C 1
.
7 alkyl group. Examples ketal groups include, but are 10 not limited to, -C(Me)(OMe) 2 , -C(Me)(OEt)2, -C(Me)(OMe)(OEt), -C(Et)(OMe) 2 , -C(Et)(OEt) 2 , and -C(Et)(OMe)(OEt). Hemiketal: -CR(OH)(OR'), where R' is as defined for hemiacetals, and R is a hemiketal substituent other than hydrogen, for example, a Cl.
7 alkyl group, a C3- 20 heterocyclyl group, 15 or a C 5
-
20 aryl group, preferably a C-.
7 alkyl group. Examples of hemiacetal groups include, but are not limited to, -C(Me)(OH)(OMe), -C(Et)(OH)(OMe), -C(Me)(OH)(OEt), and -C(Et)(OH)(OEt). Oxo (keto, -one): =0. 20 Thione (thioketone): =S. Imino (imine): =NR, wherein R is an imino substituent, for example, hydrogen, Cl.
7 alkyl group, a C 3
.
20 heterocyclyl group, or a C5-2oaryl group, preferably hydrogen or a C 1
.
7 alkyl 25 group. Examples of ester groups include, but are not limited to, =NH, =NMe, =NEt, and =NPh. Formyl (carbaldehyde, carboxaldehyde): -C(=0)H. 30 Acyl (keto): -C(=O)R, wherein R is an acyl substituent, for example, a C 1 7 alkyl group (also referred to as C 1
.
7 alkylacyl or C 1
.
7 alkanoyl), a C 3
-
2 0 heterocyclyl group (also referred to as
C
3
.
20 heterocyclylacyl), or a C 6
-
20 aryl group (also referred to as C5- 20 arylacyl), preferably a C1 alkyl group. Examples of acyl groups include, but are not limited to, -C(=O)CH 3 (acetyl), -C(=O)CH 2
CH
3 (propionyl), -C(=O)C(CH 3
)
3 (t-butyryl), and -C(=O)Ph (benzoyl, 35 phenone).
WO 03/082288 PCT/GB03/01463 - 86 Acylhalide (haloformyl, halocarbonyl): -C(=O)X, wherein X is -F, -CI, -Br, or -I, preferably -CI, -Br, or -I. Carboxy (carboxylic acid): -C(=O)OH. 5 Thiocarboxy (thiocarboxylic acid): -C(=S)SH. Thiolocarboxy (thiolocarboxylic acid): -C(=0)SH. 10 Thionocarboxy (thionocarboxylic acid): -C(=S)OH. Imidic acid: -C(=NH)OH. Hydroxamic acid: -C(=NOH)OH. 15 Ester (carboxylate, carboxylic acid ester, oxycarbonyl): -C(=O)OR, wherein R is an ester substituent, for example, a C 1
.
7 alkyl group, a C3.
20 heterocyclyl group, or a CS- 2 0 aryl group, preferably a C 1
.
7 alkyl group. Examples of ester groups include, but are not limited to,
-C(=O)OCH
3 , -C(=O)OCH 2
CH
3 , -C(=O)OC(CH 3
)
3 , and -C(=O)OPh. 20 Acyloxy (reverse ester): -OC(=O)R, wherein R is an acyloxy substituent, for example, a
CI.
7 alkyl group, a C 3
-.
2 heterocyclyl group, or a C 5
-
20 aryl group, preferably a Cl- 7 alkyl group. Examples of acyloxy groups include, but are not limited to, -OC(=O)CH 3 (acetoxy),
-OC(=O)CH
2
CH
3 , -OC(=O)C(CH 3
)
3 , -OC(=O)Ph, and -OC(=O)CH 2 Ph. 25 Oxycarboyloxy: -OC(=O)OR, wherein R is an ester substituent, for example, a C 1
.
7 alkyl group, a C 3
-
20 heterocyclyl group, or a C- 20 aryl group, preferably a C 1
.
7 alkyl group. Examples of ester groups include, but are not limited to, -OC(=O)OCH 3 ,
-OC(=O)OCH
2
CH
3 , -OC(=O)OC(CH 3
)
3 , and -OC(=O)OPh. 30 Amido (carbamoyl, carbamyl, aminocarbonyl, carboxamide): -C(=O)NRR 2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C(=O)NH 2 , -C(=O)NHCH 3 , -C(=O)N(CH 3
)
2 , -C(=O)NHCH 2
CH
3 , and -C(=O)N(CH 2
CH
3
)
2 , as well as amido groups in which R 1 and R 2 , 35 together with the nitrogen atom to which they are attached, form a heterocyclic structure WO 03/082288 PCT/GB03/01463 - 87 as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl. Acylamido (acylamino): -NR'C(=O)R 2 , wherein R 1 is an amide substituent, for example, 5 hydrogen, a C 1
.
7 alkyl group, a C 3
-
20 heterocyclyl group, or a C 5
-
20 oaryl group, preferably hydrogen or a C 1 7 alkyl group, and R 2 is an acyl substituent, for example, a C 1
.
7 alkyl group, a C 3 -2oheterocyclyl group, or a C5- 2 0 aryl group, preferably hydrogen or a C 17 alkyl group. Examples of acylamide groups include, but are not limited to, -NHC(=O)CH 3 ,
-NHC(=O)CH
2
CH
3 , and -NHC(=O)Ph. R' and R 2 may together form a cyclic structure, as 10 in, for example, succinimidyl, maleimidyl, and phthalimidyl: O N o0 0 0 / succinimidyl maleimidyl phthalimidyl Aminocarbonyloxy:
-OC(=O)NR
1 R , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups. Examples of aminocarbonyloxy groups include, 15 but are not limited to, -OC(=O)NH 2 , -OC(=O)NHMe, -OC(=O)NMe 2 , and -OC(=O)NEt 2 . Thioamido (thiocarbamyl):
-C(=S)NR
1
R
2 , wherein R 1 and R 2 are independently amino substituents, as defined for amino groups. Examples of amido groups include, but are not limited to, -C(=S)NH 2 , -C(=S)NHCH 3 , -C(=S)N(CH 3
)
2 , and -C(=S)NHCH 2 CH3. 20 Ureido: -N(R')CONR 2
R
3 wherein R 2 and R 3 are independently amino substituents, as defined for amino groups, and R1 is a ureido substituent, for example, hydrogen, a
CI.
7 alkyl group, a Ca 3
-
20 heterocyclyl group, or a C5- 20 aryl group, preferably hydrogen or a
C
1
.
7 alkyl group. Examples of ureido groups include, but are not limited to, -NHCONH 2 , 25 -NHCONHMe, -NHCONHEt, -NHCONMe 2 , -NHCONEt 2 , -NMeCONH 2 , -NMeCONHMe, -NMeCONHEt, -NMeCONMe 2 , and -NMeCONEt 2 . Guanidino: -NH-C(=NH)NH 2 . 30 Tetrazolyl: a five membered aromatic ring having four nitrogen atoms and one carbon atom, WO 03/082288 PCT/GB03/01463 - 88 IN N N Amino: -NR 1
R
2 , wherein R 1 and R 2 are independently amino substituents, for example, hydrogen, a C 1
.
7 alkyl group (also referred to as C 1
.
7 alkylamino or di-C 1
.
7 alkylamino), a 5 C 3
-.
20 heterocyclyl group, or a Cs- 20 aryl group, preferably H or a C 1 7 alkyl group, or, in the case of a "cyclic" amino group, R' and R 2 , taken together with the nitrogen atom to which they are attached, form a heterocyclic ring having from 4 to 8 ring atoms. Amino groups may be primary (-NH 2 ), secondary (-NHR 1 ), or tertiary (-NHR'R 2 ), and in cationic form, may be quaternary (- NR'R 2
R
3 ). Examples of amino groups include, but are not limited 10 to, -NH 2 , -NHCH 3 , -NHC(CH 3
)
2 , -N(CH 3
)
2 , -N(CH 2
CH
3
)
2 , and -NHPh. Examples of cyclic amino groups include, but are not limited to, aziridino, azetidino, pyrrolidino, piperidino, piperazino, morpholino, and thiomorpholino. Imino: =NR, wherein R is an imino substituent, for example, for example, hydrogen, a 15 C 1
.
7 alkyl group, a C3- 2 0 heterocyclyl group, or a C5- 2 0 aryl group, preferably H or a CI.
7 alkyl group. Examples of imino groups include, but are not limited to, =NH, =NMe, and =NEt. Amidine (amidino): -C(=NR)NR 2 , wherein each R is an amidine substituent, for example, hydrogen, a C 1 7 alkyl group, a C 3
-
20 heterocyclyl group, or a C 5
.
20 oaryl group, preferably H or 20 a C 1
.
7 alkyl group. Examples of amidine groups include, but are not limited to,
-C(=NH)NH
2 , -C(=NH)NMe 2 , and -C(=NMe)NMe 2 . Nitro: -NO 2 . 25 Cyano (nitrile, carbonitrile): -CN. Isocyano: -NC. Cyanato: -OCN. 30 Isocyanato: -NCO. Isothiocyano (isothiocyanato): -NCS. 35 Sulfhydryl (thiol, mercapto): -SH.
WO 03/082288 PCT/GB03/01463 - 89 Thioether (sulfide): -SR, wherein R is a thioether substituent, for example, a C4.
7 alkyl group (also referred to as a C 1 l 7 alkylthio group), a C 3
-
20 heterocyclyl group, or a C5- 2 0 aryl group, preferably a Cj_ 7 alkyl group. Examples of C 1
.
7 alkylthio groups include, but are not 5 limited to, -SCH 3 and -SCH 2
CH
3 . Disulfide: -SS-R, wherein R is a disulfide substituent, for example, a CI.
7 alkyl group, a
C
3
-
2 0 heterocyclyl group, or a C6-20aryl group, preferably a C 1 7 alkyl group (also referred to herein as C 1 l 7 alkyl disulfide). Examples of C 1
.
7 alkyl disulfide groups include, but are not 10 limited to, -SSCH 3 and -SSCH 2
CH
3 . Sulfine (sulfinyl, sulfoxide): -S(=O)R, wherein R is a sulfine substituent, for example, a
C
1
.
7 alkyl group, a C3- 2 0 heterocyclyl group, or a C- 20 aryl group, preferably a C 1 7 alkyl group. Examples of sulfine groups include, but are not limited to, -S(=O)CH 3 and -S(=O)CH 2
CH
3 . 15 Sulfone (sulfonyl): -S(=O) 2 R, wherein R is a sulfone substituent, for example, a Cj- 7 alkyl group, a C 3
.
2 0 heterocyclyl group, or a C5- 20 oaryl group, preferably a C 1
-
7 alkyl group, including, for example, a fluorinated or perfluorinated C 1
_
7 alkyl group. Examples of sulfone groups include, but are not limited to, -S(=O) 2
CH
3 (methanesulfonyl, mesyl), 20 -S(=O) 2
CF
3 (triflyl), -S(=O) 2 CHzCH 3 (esyl), -S(=O) 2
C
4
F
9 (nonaflyl), -S(=O) 2
CH
2
CF
3 (tresyl),
-S(=O)
2
CH
2
CH
2
NH
2 (tauryl), -S(=O) 2 Ph (phenylsulfonyl, besyl), 4-methylphenylsulfonyl (tosyl), 4-chlorophenylsulfonyl (closyl), 4-bromophenylsulfonyl (brosyl), 4-nitrophenyl (nosyl), 2-naphthalenesulfonate (napsyl), and 5-dimethylamino-naphthalen-1-ylsulfonate (dansyl). 25 Sulfinic acid (sulfino): -S(=O)OH, -SO 2 H. Sulfonic acid (sulfo): -S(=0) 2 0H, -SO 3 H. 30 Sulfinate (sulfinic acid ester): -S(=O)OR; wherein R is a sulfinate substituent, for example, a C.
7 alkyl group, a C3- 2 0 heterocyclyl group, or a Cs- 20 aryl group, preferably a C1.
7 alkyl group. Examples of sulfinate groups include, but are not limited to, -S(=0)OCH 3 (methoxysulfinyl; methyl sulfinate) and -S(=O)OCH 2
CH
3 (ethoxysulfinyl; ethyl sulfinate). 35 Sulfonate (sulfonic acid ester): -S(=O) 2 0R, wherein R is a sulfonate substituent, for example, a CI.
7 alkyl group, a Ca_ 20 heterocyclyl group, or a Cs- 20 aryl group, preferably a WO 03/082288 PCT/GB03/01463 - 90 Cs.
7 alkyl group. Examples of sulfonate groups include, but are not limited to,
-S(=O)
2 0CH 3 (methoxysulfonyl; methyl sulfonate) and -S(=0) 2
OCH
2
CH
3 (ethoxysulfonyl; ethyl sulfonate). 5 Sulfinyloxy: -OS(=O)R, wherein R is a sulfinyloxy substituent, for example, a C 1
.
7 alkyl group, a C 3
-
20 heterocyclyl group, or a C5- 20 aryl group, preferably a C 1
.
7 alkyl group. Examples of sulfinyloxy groups include, but are not limited to, -OS(=O)CH 3 and
-OS(=O)CH
2
CH
3 . 10 Sulfonyloxy: -OS(=O) 2 R, wherein R is a sulfonyloxy substituent, for example, a C 1
_
7 alkyl group, a C3- 20 heterocyclyl group, or a C 5
-
20 oaryl group, preferably a CI.
7 alkyl group. Examples of sulfonyloxy groups include, but are not limited to, -OS(=O) 2
CH
3 (mesylate) and -OS(=O) 2
CH
2
CH
3 (esylate). 15 Sulfate: -OS(=0) 2 0R; wherein R is a sulfate substituent, for example, a C1.
7 alkyl group, a
C
3
-
20 heterocyclyl group, or a C 5 -2 0 aryl group, preferably a C 1
.
7 alkyl group. Examples of sulfate groups include, but are not limited to, -OS(=O) 2 0CH 3 and -SO(=O) 2 0CH 2
CH
3 . Sulfamyl (sulfamoyl; sulfinic acid amide; sulfinamide): -S(=O)NR'R 2 , wherein R 1 and R 2 20 are independently amino substituents, as defined for amino groups. Examples of sulfamyl groups include, but are not limited to, -S(=O)NH 2 , -S(=O)NH(CH 3 ), -S(=O)N(CH 3
)
2 ,
-S(=O)NH(CH
2
CH
3 ), -S(=O)N(CH 2
CH
3
)
2 , and -S(=O)NHPh. Sulfonamido (sulfinamoyl; sulfonic acid amide; sulfonamide): -S(=O) 2
NR'R
2 , wherein R 1 25 and R 2 are independently amino substituents, as defined for amino groups. Examples of sulfonamido groups include, but are not limited to, -S(=0) 2
NH
2 , -S(=0) 2 NH(CHa),
-S(=O)
2 N(CHa) 2 , -S(=O) 2
NH(CH
2
CH
3 ), -S(=O) 2
N(CH
2
CH
3
)
2 , and -S(=O) 2 NHPh. Sulfamino: -NR'S(=O) 2 0H, wherein R 1 is an amino substituent, as defined for amino 30 groups. Examples of sulfamino groups include, but are not limited to, -NHS(=O) 2 0H and
-N(CH
3 )S(=0) 2 OH. Sulfonamino: -NR'S(=O) 2 R, wherein R 1 is an amino substituent, as defined for amino groups, and R is a sulfonamino substituent, for example, a C 1
.
7 alkyl group, a 35 C 3
-
2 oheterocyclyl group, or a C6-20aryl group, preferably a C 1
.
7 alkyl group. Examples of WO 03/082288 PCT/GB03/01463 -91 sulfonamino groups include, but are not limited to, -NHS(=0) 2
CH
3 and
-N(CH
3
)S(=O)
2
C
6 Hs. Sulfinamino: -NR 1 S(=O)R, wherein R 1 is an amino substituent, as defined for amino 5 groups, and R is a sulfinamino substituent, for example, a Cl- 7 alkyl group, a C3 2 0 heterocyclyl group, or a C5- 20 aryl group, preferably a C 1
.
7 alkyl group. Examples of sulfinamino groups include, but are not limited to, -NHS(=O)CH 3 and -N(CH 3
)S(=O)C
6
H
5 . In many cases, substituents may themselves be substituted. For example, a C 1 7 alkyl 10 group may be substituted with, for example, hydroxy (also referred to as a
C
17 hydroxyalkyl group), C 1
.
7 alkoxy (also referred to as a C 1
.
7 alkoxyalkyl group), amino (also referred to as a C1.
7 aminoalkyl group), halo (also referred to as a C4 7 haloalkyl group), carboxy (also referred to as a C, 7 carboxyalkyl group), and Cs.
20 aryl (also referred to as a C 5
-
20 aryI-C 1 -7alkyl group). 15 Similarly, a C5- 20 aryl group may be substituted with, for example, hydroxy (also referred to as a C5- 20 hydroxyaryl group), halo (also referred to as a C5- 2 0 haloaryl group), amino (also referred to as a Cs.- 20 aminoaryl group, e.g., as in aniline), C 1
-
7 alkyl (also referred to as a C, 7 alkyl-C5- 20 oaryl group, e.g., as in toluene), and C 17 alkoxy (also referred to as a 20 C..
7 alkoxy-Cs 5
-
20 aryl group, e.g., as in anisole). These and other specific examples of such substituted-substituents are described below.
C
1 _7haloalkyl group: The term "C 1
.
7 haloalkyl group," as used herein, pertains to a Cl.
7 alkyl 25 group in which at least one hydrogen atom (e.g., 1, 2, 3) has been replaced with a halogen atom (e.g., F, CI, Br, 1). If more than one hydrogen atom has been replaced with a halogen atom, the halogen atoms may independently be the same or different. Every hydrogen atom may be replaced with a halogen atom, in which case the group may conveniently be referred to as a C,.
7 perhaloalkyl group." Examples of C 1
.
7 haloalkyl 30 groups include, but are not limited to, -CF 3 , -CHF 2 , -CH 2 F, -CC13, -CBr 3 , -CH 2
CH
2 F,
-CH
2
CHF
2 , and -CH 2
CF
3 .
C.
7 haloalkoxy: -OR, wherein R is a Cl 7 haloalkyl group. Examples of C 1
.
7 haloalkoxy groups include, but are not limited to, -OCF 3 , -OCHF 2 , -OCH 2 F, -OCCi3, -OCBr 3 , 35 -OCH 2
CH
2 F, -OCH 2
CHF
2 , and -OCH 2
CF
3
.
WO 03/082288 PCT/GB03/01463 - 92 C.
7 hydroxyalkyl: The term "Cl 7 hydroxyalkyl group," as used herein, pertains to a
C
1 7 alkyl group in which at least one hydrogen atom has been replaced with a hydroxy group. Examples of C_ 7 hydroxyalkyl groups include, but are not limited to,
-CH
2
OH,-CH
2
CH
2 OH, and -CH(OH)CH20H. 5
C
1 7 carboxyalkyl: The term "Cl.
7 carboxyalkyl group," as used herein, pertains to a
CI
7 alkyl group in which at least one hydrogen atom has been replaced with a carboxy group. Examples of C 17 carboxyalkyl groups include, but are not limited to, -CH 2 COOH and -CH 2
CH
2 COOH. 10 Cl- 7 aminoalkyl: The term "Cl.
7 aminoalkyl group," as used herein, pertains to a C 1
.
7 alkyl group in which at least one hydrogen atom has been replaced with an amino group. Examples of C_ 7 aminoalkyl groups include, but are not limited to, -CH 2
NH
2
,-CH
2
CH
2
NH
2 , and -CH 2
CH
2
N(CH
3
)
2 . 15
CI
7 aminoalkylamino: The term "Cl 7 aminoalkylamino," as used herein, pertains to an amino group, -NR 1
R
2 , in which one of the substituents, R' or R 2 , is itself a C 1
-
7 aminoalkyl group (-Cj 7 alkyl-NR 1
R
2 ). The C.
7 aminoalkylamino may be represented, for example, by the formula -NR'-C.
7 alkyl-NRR 2 . Examples of amino-Cl.
7 alkylamino groups include, but 20 are not limited to, groups of the formula -NR'(CH 2 )nNR'R 2 , where n is 1 to 6, for example,
-NHCH
2
NH
2 , -NH(CH 2
)
2
NH
2 , -NH(CH 2
)
3
NH
2 , -NH(CH 2
)
4
NH
2 , -NH(CH 2
)
5
NH
2 ,
-NH(CH
2
)
6
NH
2 , -NHCH 2 NH(Me), -NH(CH 2
)
2 NH(Me), -NH(CH 2
)
3 NH(Me),
-NH(CH
2
)
4 NH(Me), -NH(CH 2
)
5 NH(Me), -NH(CH 2
)
6 NH(Me), -NHCH 2 NH(Et),
-NH(CH
2
)
2 NH(Et), -NH(CH 2
)
3 NH(Et), -NH(CH 2
)
4 NH(Et), -NH(CH 2
)
5 NH(Et), and 25 -NH(CH 2
)
6 NH(Et).
CI
7 alkyl-C5- 20 aryl: The term "Cl 7 alkyl-C 5
-
20 aryl," as used herein, describes certain C- 20 aryl groups which have been substituted with a C.
7 alkyl group. Examples of such groups include, but are not limited to, tolyl (from toluene), xylyl (from xylene), mesityl (from 30 mesitylene), and cumenyl (or cumyl, from cumene), and duryl (from durene).
C
7 alkyl-C5- 20 aryloxy: The term "C 7 alkyl-C5- 20 aryloxy," as used herein, describes certain
C
5
-.
20 aryloxy groups which have been substituted with a C 17 alkyl group. Examples of such groups include, but are not limited to, tolyloxy, xylyloxy, mesityloxy, cumenyloxy, and 35 duryloxy.
WO 03/082288 PCT/GB03/01463 - 93 C 5
-
20 aryI-C 1
.
7 alkyl: The term "C5 20 oaryI-C 1 7 alkyl," as used herein, describers certain
C
1
.
7 alkyl groups which have been substituted with a Cs-.
20 aryl group. Examples of such groups include, but are not limited to, benzyl (phenylmethyl, PhCH 2 -), benzhydryl (Ph 2 CH-), trityl (triphenylmethyl, Ph 3 C-), phenethyl (phenylethyl, Ph-CH 2
CH
2 -), styryl 5 (Ph-CH=CH-), cinnamyl (Ph-CH=CH-CH 2 -).
C-
2 0 aryl-C 1
.
7 alkoxy: The term "CS- 20 aryl-C 1 -7alkoxy," as used herein, describes certain
C
1 .7alkoxy groups which have been substituted with a C5- 20 aryl group. Examples of such groups include, but are not limited to, benzyloxy, benzhydryloxy, trityloxy, phenethoxy, 10 styryloxy, and cimmamyloxy.
C
5
-
20 haloaryl: The term "Cs 5
-
20 haloaryl," as used herein, describes certain C5-2oaryl groups which have been substituted with one or more halo groups. Examples of such groups include, but are not limited to, halophenyl (e.g., fluorophenyl, chlorophenyl, bromophenyl, 15 or iodophenyl, whether ortho-, meta-, or para-substituted), dihalophenyl, trihalophenyl, tetrahalophenyl, and pentahalophenyl. Bidentate Substituents 20 The term "bidentate substituents," as used herein, pertains to substituents which have two points of covalent attachment, and which act as a linking group between two other moieties. In some cases (A), a bidentate substituent is covalently bound to a single atom. In some 25 cases (B), a bidentate substituent is covalently bound to two different atoms, and so serves as a linking group therebetween. (A) (B) A-- bidentate group-A 2 bidentate group Within (B), in some cases (C), a bidentate substituent is covalently bound to two different 30 atoms, which themselves are not otherwise covalently linked (directly, or via intermediate groups). In some cases (D), a bidentate substituent is covalently bound to two different atoms, which themselves are already covalently linked (directly, or via intermediate groups); in such cases, a cyclic structure results. In some cases, the bidentate group is covalently bound to vicinal atoms, that is, adjacent atoms, in the parent group.
WO 03/082288 PCT/GB03/01463 -94 bidentate group (C) A-- bidentate group-A 2 (D) A bidentate group
A
2 Al A 2 In some cases (A and D), the bidentage group, together with the atom(s) to which it is attached (and any intervening atoms, if present) form an additional cyclic structure. In this 5 way, the bidentate substituent may give rise to a cyclic or polycyclic (e.g., fused, bridged, spiro) structure, which may be aromatic. Examples of bidentate groups include, but are not limited to, C 1
_
7 alkylene groups,
C
3
-
20 heterocyclylene groups, and C5- 20 arylene groups, and substituted forms thereof. 10 Alkvylene Alkylene: The term "alkylene," as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each 15 of two different carbon atoms, of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated. Thus, the term "alkylene" includes the sub-classes alkenylene, alkynylene, cycloalkylene, etc., discussed below. 20 In this context, the prefixes (e.g., C14, C4-7, C1-2o, C2- 7 , C 3
-
7 , etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "C 14 alkylene," as used herein, pertains to an alkylene group having from 1 to 4 carbon atoms. Examples of groups of alkylene groups include C 1 4alkylene ("lower alkylene"), C 1 .7alkylene, and
C.-
20 alkylene. 25 Examples of linear saturated C 1
.
7 alkylene groups include, but are not limited to, -(CH 2 )n where n is an integer from 1 to 7, for example, -CH 2 - (methylene), -CH 2
CH
2 - (ethylene),
-CH
2
CH
2
CH
2 - (propylene), and -CH 2
CH
2
CH
2
CH
2 - (butylene). 30 Examples of branched saturated C 1 -7alkylene groups include, but are not limited to,
-CH(CH
3 )-, -CH(CH 3
)CH
2 -, -CH(CH 3
)CH
2
CH
2 -, -CH(CH 3
)CH
2
CH
2
CH
2 -, -CH 2
CH(CH
3
)CH
2 -,
-CH
2
CH(CH
3
)CH
2
CH
2 -, -CH(CH 2
CH
3 )-, -CH(CH 2
CH
3
)CH
2 -, and -CH 2
CH(CH
2
CH
3
)CH
2 -. Examples of linear partially unsaturated C, 7 alkylene groups include, but is not limited to, 35 -CH=CH- (vinylene), -CH=CH-CH 2 -, -CH=CH-CH 2
-CH
2 -, -CH=CH-CH 2
-CH
2
-CH
2
-,
WO 03/082288 PCT/GB03/01463 - 95 -CH=CH-CH=CH-, -CH=CH-CH=CH-CH 2 -, -CH=CH-CH=CH-CH 2
-CH
2 -, -CH=CH
CH
2 -CH=CH-, and -CH=CH-CH 2
-CH
2 -CH=CH-. Examples of branched partially unsaturated C 1
_
7 alkylene groups include, but is not limited 5 to, -C(CH 3 )=CH-, -C(CH 3
)=CH-CH
2 -, and -CH=CH-CH(CH 3 )-. Examples of alicyclic saturated C1.
7 alkylene groups include, but are not limited to, cyclopentylene (e.g., cyclopent-1,3-ylene), and cyclohexylene (e.g., cyclohex-1,4-ylene). 10 Examples of alicyclic partially unsaturated C 1
.
7 alkylene groups include, but are not limited to, cyclopentenylene (e.g., 4-cyclopenten-1,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-1,4-ylene; 3-cyclohexen-1,2-ylene; 2,5-cyclohexadien-1,4-ylene). Arylene 15 Arylene: The term "arylene," as used herein, pertains to a bidentate moiety obtained by removing two hydrogen atoms, one from each of two different aromatic ring atoms of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 5 to 7 ring atoms. 20 In this context, the prefixes (e.g., C3-20, C9-7, C5-6, etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "Cs.
5 6 arylene," as used herein, pertains to an arylene group having 5 or 6 ring atoms. Examples of groups of arylene groups include C 3
-
2 0 arylene, C 3
-
1 2 arylene, C5- 12 arylene, 25 C.
7 arylene, and C 5 -6arylene. The ring atoms may be all carbon atoms, as in "carboarylene groups" (e.g., C5- 20 carboarylene). 30 Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroarylene groups" (e.g., Cs.- 20 heteroarylene). Examples of CS- 2 0 arylene groups which do not have ring heteroatoms (i.e., C 5
-
20 carboarylene groups) include, but are not limited to, those derived from the 35 compounds discussed above in regard to carboaryl groups.
WO 03/082288 PCT/GB03/01463 -96 Examples of C.- 2 0 heteroarylene groups include, but are not limited to, those derived from the compounds discussed above in regard to heteroaryl groups. Includes Other Forms 5 Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO-), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes 10 the protonated form (-N'HR 1
R
2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-0-), a salt or solvate thereof, as well as conventional protected forms. 15 Isomers, Salts, Solvates, Protected Forms, and Prodrugs Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r 20 forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and I-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and 3-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms"). 25 Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH 3 , is not to be construed as 30 a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1
.
7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, 35 meta-, and para-methoxyphenyl).
WO 03/082288 PCT/GB03/01463 -97 The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amidelimino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro. H H+ H ,O , OH H O I / CC \ /- % /C=C 5 keto enol enolate Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12C, 13C, and 14C; O may be in any 10 isotopic form, including 160 and 180; and the like. Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional 15 crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner. Unless otherwise specified, a reference to a particular compound also includes ionic, salt, 20 solvate, and protected forms of thereof, for example, as discussed below. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically 25 Acceptable Salts," J. Pharm. Sci., Vol. 66, pp. 1-19. For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO-), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + 30 and K*, alkaline earth cations such as Ca 2 + and Mg 2 , and other cations such as Al+ 3 . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4
+
) and substituted ammonium ions (e.g., NH 3 R', NH 2
R
2 *, NHR3
+
, NR4+). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, WO 03/082288 PCT/GB03/01463 - 98 ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3
)
4 '. 5 If the compound is cationic, or has a functional group which may be cationic (e.g., -NH 2 may be -NH 3 '), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous. 10 Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesulfonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, 15 isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose. 20 It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the active compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a 25 hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive 30 functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group 35 (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive WO 03/082288 PCT/GB03/01463 - 99 functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999). 5 A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore 10 unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality. 15 For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester
(-OC(=O)CH
3 , -OAc). 20 For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR) 2 ) or ketal (R 2
C(OR)
2 ), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR) 2 ), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid. 25 For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 CeHe, -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CHs)3, -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CH) 2
C
6
H
4
C
6 H, -NH-Bpoc), as a 9 30 fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulphonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O*). 35 For example, a carboxylic acid group may be protected as an ester for example, as: an
CI.
7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a CI_ 7 haloalkyl ester (e.g., a WO 03/082288 PCT/GB03/01463 - 100
C
1 l 7 trihaloalkyl ester); a triC 1 7 alkylsilyl-C 1
.
7 alkyl ester; or a C- 20 aryl-Cl.
7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide. For example, a thiol group may be protected as a thioether (-SR), for example, as: a 5 benzyl thioether; an acetamidomethyl ether (-S-CH 2
NHC(=O)CH
3 ). It may be convenient or desirable to prepare, purify, and/or handle the active compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired active compound. Typically, the 10 prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties. For example, some prodrugs are esters of the active compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is 15 cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required. 20 Examples of such metabolically labile esters include those of the formula -C(=O)OR wherein R is:
C
1
.
7 alkyl (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);
CI.
7 aminoalkyl (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-Cl.
7 alkyl 25 (e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 30 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 35 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; WO 03/082288 PCT/GB03/01463 -101 1-(4-tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl). 5 Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative. 10 Acronyms For convenience, many chemical moieties are represented using well known abbreviations, including but not limited to, methyl (Me), ethyl (Et), n-propyl (nPr), iso propyl (iPr), n-butyl (nBu), sec-butyl (sBu), iso-butyl (iBu), tert-butyl (tBu), n-hexyl (nHex), 15 cyclohexyl (cHex), phenyl (Ph), biphenyl (biPh), benzyl (Bn), naphthyl (naph), methoxy (MeO), ethoxy (EtO), benzoyl (Bz), and acetyl (Ac). For convenience, many chemical compounds are represented using well known abbreviations, including but not limited to, methanol (MeOH), ethanol (EtOH), iso 20 propanol (i-PrOH), methyl ethyl ketone (MEK), ether or diethyl ether (Et 2 0), acetic acid (AcOH), dichloromethane (methylene chloride, DCM), acetonitrile (ACN), trifluoroacetic acid (TFA), dimethylformamide (DMF), tetrahydrofuran (THF), and dimethylsulfoxide (DMSO). 25 Synthesis Methods for the chemical synthesis of compounds of the present invention are described herein. These methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention. 30 The compounds of the present invention may be prepared, for example, by the methods described herein, or by adapting these or other well known methods in well known ways. In one method, a suitable chloro sulfonate (also having a protected carboxylic acid group, 35 e.g., ester) is prepared, for example, from an aldehyde, by reaction with, e.g., H 2
SO
4 and
SO
3 , followed by reaction wtih, e.g., a suitable phosphate, e.g., (MeO) 2 P(O)R, followed by WO 03/082288 PCT/GB03/01463 - 102 reaction with, e.g., SO 2
C
2 . An example of such a method is illustrated in the following scheme. Scheme 1
H
2
SO
4 +SOz O j 1 CHO NaOS X CHO N O \ 10 (MeO) 2 P(0)CH 2 COOMe 2 K,CO,O NaoS, COOMe O Cl \\0 5 3 The chloro sulfonate is then reacted with a suitable piperazine, to give the corresponding piperazino sulfonamide. An example of such a method is illustrated in the following scheme (see also Method A below). 10 Scheme 2 NH 'NN C S C eRS COOMe COOMe0 0R The protected carboxylic acid group (e.g., ester) is then converted to a hydroxamic acid, 15 for example, by deprotection with NaOH, followed by reaction with (COC1) 2 , followed by reaction with NH 2 OH. An example of such a method is illustrated in the following scheme (see also Methods B, C, and D below).
WO 03/082288 PCT/GB03/01463 - 103 Scheme 3 O, . O\ COO H 0 I0 o\I 5 NSo COOMe NaOH NSCOOH 0 r 0 R NJRN Oj CO 6 0 J (COCI), NO ' OC R NPX 0N, NH2OH N\\O O R HN In another method, a suitable phenylacrylic acid is reacted with, e.g., chlorosulfonic acid 5 (HSO 3 CI) to form the corresponding para-chlorosulfonylphenyl acrylic acid, which is then reacted with piperazine to form the corresponding piperazino sulfonamide. An example of such a method is illustrated in the following scheme. Scheme 4 SCOOH o 'COOH
HSO
3 CI II I,-( 10 7 c,-- 8 0 NH ,NJ 0 COOH R-N \_N-S- r 9 10 0 The carboxylic acid group (e.g., ester) is then converted to a chloroacyl group, for example, by reaction with (COCI) 2 , and is then converted to a hydroxamic acid by reaction with, for example, NH 2 OH. An example of such a method is illustrated in the following scheme. 15 WO 03/082288 PCT/GB03/01463 - 104 Scheme 5 O o ... COOH 0 C 101,(COCI), CI R-N - R-N N-S 10 S0o NH 2 0H 10 H ------ *-R-N N-S x PX H 0 In another method, suitable piperazine compounds are prepared by reaction of piperazine 5 with a suitable carboxylic acid (R-COOH), for example, in the presence of hydroxybenzotriazole, to give the corresponding amide. An example of such a method is illustrated in the following scheme (see also Method E below). Scheme 6 O SHOBT, DCC R NNH HN \2NH + R O -\N H _/ R OH 10o 11 12 13 In another method, a suitably protected (e.g., t-butoxycarbonyl protected) piperazine is reacted with, for example, a haloacyl compound (e.g,. chloroacylbenzene, PhCOCI) or a 15 suitable carboxylic acid (R-COOH), to give the corresponding amide, followed by deprotection (e.g., with HCl/MeOH and NaOH). An example of such a method is illustrated in the following scheme (see also Methods F and G, below). Scheme 7 0 CDI/DMFA 0 R -Ci- 0 0 HN N O R N N 14 OH15 14 12 1) HCI/MeOH o 2) NaOH R 'N NH 20 13 WO 03/082288 PCT/GB03/01463 - 105 In another method, the piperazine amide is hydrogenated, for example, by reaction with LiAIH4/THF, to give the corresponding N-substituted piperazine. An example of such a method is illustrated in the following scheme (see also Method H below). 5 Scheme 8 O RtN-NH LiA]H 4 /THF R N NH 13 16 A number of N-substituted piperazine compounds are commercially available, and/or can 10 be readily prepared using well known methods. Examples of such compounds include the following: N-phenylpiperazine (17a); 1 -(diphenylmethyl)piperazine (17b); 1-(2-methoxyphenyl)piperazine hydrochloride (17c); 15 1-(2-chlorophenyl)piperazine (17d); 1-(3-chlorophenyl)piperazine (17e); 1-(4-methoxyphenyl)piperazine (17f); 1-(3-methoxyphenyl)piperazine (17g); 1-(4-nitrophenyl)piperazine (17h); 20 1-(3,4-dichlorophenyl)piperazine (171); 1-(4-fluorophenyl)piperazine (_17); 1-(4-chlorophenyl)piperazine (17k); 1-(2-pyridinyl)piperazine (171); 2-(1-piperazinyl)pyrimidine (17m); and 25 1-(3,4-dimethylphenyl)piperazine (17n). In another method, a suitable carboxylic acid (also having a protected carboxylic acid group) is reacted with a suitable piperazine, for example, in the presence of carbonyldiimidazole (CDI). An example of such a method is illustrated in the following 30 scheme (see also Methods J, K, and L, below).
WO 03/082288 PCT/GB03/01463 - 106 Scheme 9 NHN O COOR + rO N R'COOR 0 R
N
J 0 18 13,16,17 19 The protected carboxylic acid group (e.g., ester) is then converted to a hydroxamic acid, 5 for example, by reaction with NH 2 OH and NaOMe in methanol. An example of such a method is illustrated in the following scheme (see also Methods Q and R, below). Scheme 10 R, NaOMe/MeOH RN NO|R NH 2 0H I NI H N COOR . N N' OH 19 o PX o 0 10 In another method, a suitable carboxylic acid (also having a protected carboxylic acid group) is reacted with (COCI) 2 and H 2 NOBn, to give the corresponding benzyloxyamide. The protected carboxylic acid group is then deprotected, for example, by reaction with NaOH, and then reacted with a suitable piperazine to give the corresponding piperazine 15 amide. The benzyloxyamide is then converted to a carbamic acid, for example, by reaction with H 2 over Pd(C). An example of such a method is illustrated in the following scheme (see also Methods M, N, P, and S, below). Scheme 11 1) (COC) 2 2) H 2 NOBn H 18 OOR Bn2H NN Ol COOR 20 18 0 0 NaOH
H
2 0/THF H .Bn, N 11n COOH 21 O , HN N-R N H l SBn.. N N J 22 O O0 ,R N
H
2 IPd(C) HO N N N PX 20 O O WO 03/082288 PCT/GB03/01463 - 107 Use The present invention provides active compounds, specifically, active carbamic acids, as 5 described herein. The term "active," as used herein, specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity. 10 The present invention also provides active compounds which inhibit HDAC activity. The present invention also provides methods of inhibiting HDAC in a cell, comprising contacting said cell with an effective amount of an active compound. Such a method may 15 be practised in vitro or in vivo. In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo. Preferably, the active compound is provided in the form of a pharmaceutically acceptable composition. The term "inhibiting HDAC," as used herein, includes: inhibiting HDAC activity; inhibiting 20 the formation of HDAC complexes; and inhibiting the activity of HDAC complexes. One of ordinary skill in the art is readily able to determine whether or not a candidate compound inhibits HDAC activity. For example, one assay which may conveniently be used in order to assess the HDAC inhibition offered by a particular compound is 25 described in the examples below. The present invention also provides active compounds which (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these. 30 Thus, the present invention also provides methods of (a) regulating (e.g., inhibiting) cell proliferation; (b) inhibiting cell cycle progression; (c) promoting apoptosis; or (d) a combination of one or more of these, in vitro or in vivo, comprising contacting a cell with an effective amount of an active compound, as described herein. 35 WO 03/082288 PCT/GB03/01463 - 108 One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulate (e.g., inhibit) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described in the examples below. 5 For example, a sample of cells (e.g., from a tumour) may be grown in vitro and an active compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the active compound is found to exert an 10 influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type. Methods of Treatment, Etc. 15 The invention further provides methods of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition. 20 The invention further provides active compounds for use in a method of treatment of the human or animal body by therapy, for example, in the treatment of a condition mediated by HDAC, a condition known to be treated by HDAC inhibitors (such as, e.g., trichostatin A), cancer, a proliferative condition, or other condition as described herein. 25 The invention further provides the use of an active compound for the manufacture of a medicament, for example, for the treatment of a condition mediated by HDAC, a condition known to be treated by HDAC inhibitors (such as, e.g., trichostatin A), cancer, a proliferative condition, or other condition as described herein. 30 Treatment The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the 35 inhibition of the progress of the condition, and includes a reduction in the rate of progress, WO 03/082288 PCT/GB03/01463 - 109 a halt in the rate of progress, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. The term "therapeutically-effective amount," as used herein, pertains to that amount of an 5 active compound, or a material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio. The term "treatment" includes combination treatments and therapies, in which two or 10 more treatments or therapies are combined, for example, sequentially or simultaneously. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; and gene therapy. 15 Active compounds may also be used, as described above, in combination therapies, that is, in conjunction with other agents, for example, cytotoxic agents. Anti-HDAC Applications 20 The present invention also provides active compounds which are anti-HDAC agents, and which treat a condition mediated by HDAC. The term "a condition mediated by HDAC," as used herein pertains to a condition in which 25 HDAC and/or the action of HDAC is important or necessary, e.g., for the onset, progress, expression, etc. of that condition, or a condition which is known to be treated by HDAC inhibitors (such as, e.g., trichostatin A). Examples of such conditions include, but are not limited to, the following: 30 Cancer (see, e.g., Vigushin et al., 2001). Psoriasis (see, e.g., lavarone et al., 1999). 35 Fibroproliferative disorders (e.g., liver fibrosis) (see, e.g., Niki et al., 1999; Corneil et al., 1998).
WO 03/082288 PCT/GB03/01463 -110 Smooth muscle proliferative disorder (e.g., atherosclerosis, restenosis) (see, e.g., Kimura et al., 1994). 5 Neurodegenative diseases (e.g., Alzheimer's, Parkinson's, Huntington's chorea, amyotropic lateral sclerosis, spino-cerebellar degeneration) (see, e.g., Kuusisto et al., 2001). Inflammatory disease (e.g., osteoarthritis, rheumatoid arthritis) (see, e.g., Dangond et al., 10 1998; Takahashi et al., 1996). Diseases involving angiogenesis (e.g., cancer, rheumatoid arthritis, psoriasis, diabetic retinopathy) (see, e.g., Kim et al., 2001). 15 Haematopoietic disorders (e.g., anaemia, sickle cell anaemia, thalassaeimia) (see, e.g., McCaffrey et al., 1997). Fungal infection (see, e.g., Bernstein et al., 2000; Tsuji et al., 1976). 20 Parasitic infection (e.g., malaria, trypanosomiasis, helminthiasis, protozoal infections (see, e.g., Andrews et al., 2000). Bacterial infection (see, e.g., Onishi et al., 1996). 25 Viral infection (see, e.g., Chang et al., 2000). Conditions treatable by immune modulation (e.g., multiple sclerosis, autoimmune diabetes, lupus, atopic dermatitis, allergies, asthma, allergic rhinitis, inflammatory bowel disease; and for improving grafting of transplants) (see, e.g., Dangond et al., 1998; 30 Takahashi et al., 1996). One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a condition mediated by HDAC for any particular cell type. For example, assays which may conveniently be used to assess the activity offered by a particular 35 compound are described in the examples below.
WO 03/082288 PCT/GB03/01463 -111 Anticancer Applications The present invention also provides active compounds which are anticancer agents, and treat cancer. 5 Thus, the present invention also provides methods of treating cancer, comprising administering to a subject in need of treatment a therapeutically-effective amount of an active compound, as described herein, preferably in the form of a pharmaceutical composition. 10 One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described in the examples below. 15 The term "anticancer agent" as used herein, pertains to a compound which treats a cancer (i.e., a compound which is useful in the treatment of a cancer). The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of 20 angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death). Exampes of cancers are discussed below. 25 Antiproliferative Applications The present invention also provides active compounds which are antiproliferative agents. The term "antiproliferative agent" as used herein, pertain to a compound which treats a proliferative condition (i.e., a compound which is useful in the treatment of a proliferative 30 condition). Thus, the present invention also provides methods of treating a proliferative condition, comprising administering to a subject in need of treatment a therapeutically-effective amount of an active compound, as described herein, preferably in the form of a 35 pharmaceutical composition.
WO 03/082288 PCT/GB03/01463 -112 One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a proliferative condition for any particular cell type. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described in the examples below. 5 The terms "cell proliferation," "proliferative condition," "proliferative disorder," and "proliferative disease," are used interchangeably herein and pertain to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth, whether in vitro or in vivo. 10 Examples of proliferative conditions include, but are not limited to, benign, pre-malignant, and malignant cellular proliferation, including but not limited to, neoplasms and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (e.g., lung cancer, small cell lung cancer, gastrointestinal cancer, bowel cancer, colon cancer, breast carinoma, 15 ovarian carcinoma, prostate cancer, testicular cancer, liver cancer, kidney cancer, bladder cancer, pancreas cancer, brain cancer, sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma), leukemias, psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), and atherosclerosis. 20 Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin. Additional Uses 25 Active compounds may also be used as cell culture additives to inhibit HDAC, for example, in order to regulate (e.g., inhibit) cell proliferation in vitro. Active compounds may also be used as part of an in vitro assay, for example, in order to 30 determine whether a candidate host is likely to benefit from treatment with the compound in question. Active compounds may also be used as a standard, for example, in an assay, in order to identify other active compounds, other HDAC inhibitors, other anticancer agents, other 35 antiproliferative agents, etc.
WO 03/082288 PCT/GB03/01463 -113 The compounds of the present invention may also be used in methods of improving protein production by cultured cells (see, e.g., Furukawa et al., 1998). Routes of Administration 5 The active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/ peripherally or topically (i.e., at the site of desired action). 10 Routes of administration include, but are not limited to, oral (e.g, by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by 15 pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. 20 The Subject The subject may be a prokaryote (e.g., bacteria) or a eukaryote (e.g., protoctista, fungi, plants, animals). 25 The subject may be a protoctista, an alga, or a protozoan. The subject may be a plant, an angiosperm, a dicotyledon, a monocotyledon, a gymnosperm, a conifer, a ginkgo, a cycad, a fern, a horsetail, a clubmoss, a liverwort, or a 30 moss. The subject may be an animal. The subject may be a chordate, an invertebrate, an echinoderm (e.g., starfish, sea 35 urchins, brittlestars), an arthropod, an annelid (segmented worms) (e.g., earthworms, lugworms, leeches), a mollusk (cephalopods (e.g., squids, octopi), pelecypods (e.g., WO 03/082288 PCT/GB03/01463 -114 oysters, mussels, clams), gastropods (e.g., snails, slugs)), a nematode (round worms), a platyhelminthes (flatworms) (e.g., planarians, flukes, tapeworms), a cnidaria (e.g., jelly fish, sea anemones, corals), or a porifera (e.g., sponges). 5 The subject may be an arthropod, an insect (e.g., beetles, butterflies, moths), a chilopoda (centipedes), a diplopoda (millipedes), a crustacean (e.g., shrimps, crabs, lobsters), or an arachnid (e.g., spiders, scorpions, mites). The subject may be a chordate, a vertebrate, a mammal, a bird, a reptile (e.g., snakes, 10 lizards, crocodiles), an amphibian (e.g., frogs, toads), a bony fish (e.g., salmon, plaice, eel, lungfish), a cartilaginous fish (e.g., sharks, rays), or a jawless fish (e.g., lampreys, hagfish). The subject may be a mammal, a placental mammal, a marsupial (e.g., kangaroo, 15 wombat), a monotreme (e.g., duckbilled platypus), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a 20 human. Furthermore, the subject may be any of its forms of development, for example, a spore, a seed, an egg, a larva, a pupa, or a foetus. 25 Formulations While it is possible for the active compound to be used (e.g., administered) alone, it is often preferable to present it as a formulation. 30 Thus, one aspect of the present invention pertains to a composition comprising a compound, as described herein, and a carrier. In one embodiment, the composition is a pharmaceutical composition (e.g., formulation, preparation, medicament) comprising a compound, as described herein, and a 35 pharmaceutically acceptable carrier.
WO 03/082288 PCT/GB03/01463 -115 In one embodiment, the composition is a pharmaceutical composition comprising at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, 5 preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. In one embodiment, the composition further comprises other active agents, for example, other therapeutic or prophylactic agents. 10 Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts. See, for example, Handbook fo Pharmaceutical Additives, 2nd Edition (eds. M. Ash and 1. Ash), 2001 (Synapse Information Resources, Inc., Endicott, New York, USA), Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, 15 Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, 1994. Another aspect of the present invention pertains to methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more other pharmaceutically acceptable ingredients well known to 20 those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the active compound. The term "pharmaceutically acceptable" as used herein pertains to compounds, 25 ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the 30 other ingredients of the formulation. The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations 35 are prepared by uniformly and intimately bringing into association the active compound WO 03/082288 PCT/GB03/01463 -116 with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary. The formulation may be prepared to provide for rapid or slow release; immediate, 5 delayed, timed, or sustained release; or a combination thereof. Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., 10 coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols. Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, 15 or the like which is impregnated with one or more active compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in a the form of a depot or reservoir. 20 The active compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The active compound may be presented in a liposome or other microparticulate which is designed to target the active compound, for example, to blood components or one or more organs. 25 Formulations suitable for oral administration (e.g, by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses. 30 Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the active compound in a flavored basis, usually sucrose and acacia or tragacanth. Pastilles typically comprise the active compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the active 35 compound in a suitable liquid carrier.
WO 03/082288 PCT/GB03/01463 -117 Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills. Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., 5 aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Formulations suitable for non-oral transmucosal administration include liquids, solutions 10 (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs. Formulations suitable for transdermal administration include gels, pastes, ointments, 15 creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs. Tablets may be made by conventional means, e.g., compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by 20 compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked 25 povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets 30 may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the 35 stomach.
WO 03/082288 PCT/GB03/01463 -118 Ointments are typically prepared from the active compound and a paraffinic or a water miscible ointment base. Creams are typically prepared from the active compound and an oil-in-water cream base. 5 If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other 10 affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues. Emulsions are typically prepared from the active compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may 15 comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called.emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base 20 which forms the oily dispersed phase of the cream formulations. Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic 25 properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of 30 coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin andlor liquid paraffin or other mineral oils can be used. 35 WO 03/082288 PCT/GB03/01463 -119 Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the active compound. 5 Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. 10 Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases. 15 Formulations suitable for ocular administration include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound. 20 Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema. 25 Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate. Formulations suitable for parenteral administration (e.g., by injection), include aqueous or 30 non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the active compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the 35 formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable WO 03/082288 PCT/GB03/01463 - 120 oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the active compound in the liquid is from about 1 ng/ml to about 10 pg/ml, for example from about 10 ng/ml to about 1 pg/ml. The formulations may 5 be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets. 10 Dosage It will be appreciated by one of skill in the art that appropriate dosages of the active compounds, and compositions comprising the active compounds, can vary from patient to 15 patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials 20 used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing 25 substantial harmful or deleterious side-effects. Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to 30 those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician. 35 In general, a suitable dose of the active compound is in the range of about 0.1 to about 250 mg per kilogram body weight of the subject per day. Where the active compound is a WO 03/082288 PCT/GB03/01463 -121 salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately. 5 Kits One aspect of the invention pertains to a kit comprising (a) the active ingredient, preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the active 10 compound, etc. The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.
WO 03/082288 PCT/GB03/01463 -122 EXAMPLES The following are examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. 5 General 'H NMR spectra were recorded at ambient temperature with WH-90/DS or Mercury 200 (Varian) spectrometers. The HPLC measurements were performed on a Gilson Model 10 302 system equipped with a spectrophotometer. Elemental analyses were obtained with a Carlo Erba EA 1108 instrument. Melting points were measured on a "Boatius" micro melting point apparatus and are uncorrected. Silicagel, 0.035-0.070 mm, (Acros) was employed for column chromatography. All the solvents were purified before use by routine techniques. To isolate reaction products the solvents were removed by 15 evaporation using a vacuum rotary evaporator, the water bath temperature not exceeding 400C. Various reagents were purchased from Sigma-Aldrich (The Old Brickyard, New Road, Gillingham, Dorset, UK), Acros Organics (Janssens Pharmaceuticalaan 3A, 2440 Geel, 20 Belgium), Lancaster Synthesis Ltd. (Eastgate, White Lund, Morecambe, Lancashire, LA3 3DY, UK), and Bapeks Ltd. (Riga, Latvia). Example 1 3-Formylbenzenesulfonic acid, sodium salt (1) 25 Oleum (5 mL) was placed in a reaction vessel and benzaldehyde (2.00 g, 18.84 mmol) was slowly added not exceeding the temperature of the reaction mixture more than 300C. The obtained solution was stirred at 400C for 10 hours and at ambient temperature overnight. The reaction mixture was poured into ice and extracted with ethyl acetate. The 30 aqueous phase was treated with CaCO 3 until the evolution of CO 2 ceased (pH~6-7), then the precipitated CaSO 4 was filtered off and washed with water. The filtrate was treated with Na 2
CO
3 until the pH of the reaction medium increased to pH 8, obtained CaCO 3 was filtered off and water solution was evaporated in vacuum. The residue was washed with methanol, the washings were evaporated and the residue was dried in desiccator over 35 P 2 0 5 affording the title compound (2.00 g, 51%). 'H NMR (D20), 5: 7.56-8.40 (4H, m); 10.04 (1H, s).
WO 03/082288 PCT/GB03/01463 - 123 Example 2 3-(3-Sulfophenyl)acrylic acid methyl ester, sodium salt (2) 5 Sodium salt of 3-formylbenzenesulfonic acid (1) (1.00 g, 4.80 mmol), potassium carbonate (1.32 g, 9.56 mmol), trimethyl phosphonoacetate (1.05 g, 5.77 mmol) and water (2 mL) were stirred at ambient temperature for 30 min, and the precipitated solid was filtered and washed with methanol. The filtrate was evaporated and to give the title compound as a white solid (0.70 g, 55%). 1 H NMR (DMSO-d 6 , HMDSO), 5: 3.68 (3H, s); 10 6.51 (1H, d, J=16.0 Hz); 7.30-7.88 (5H, m). Example 3 3-(3-Chlorosulfonylphenyl)acrylic acid methyl ester (3) 15 To the sodium salt of 3-(3-sulfophenyl)acrylic acid methyl ester (2) (0.670 g, 2.53 mmol) benzene (2 mL), thionyl chloride (1.508 g, 0.9 mL, 12.67 mmol) and 3 drops of dimethylformamide were added and the resultant suspension was stirred at reflux for one hour. The reaction mixture was evaporated, the residue was dissolved in benzene (3 mL), filtered and the filtrate was evaporated to give the title compound (0.640 g, 97%). 20 Method A - General Synthesis of methyl (E)-3-(3-{[4-substituted 1 piperazinylsulfonyl}phenyl)-2-propenoates (4a-1) A solution of 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) (0.40 g, 1.53 mmol) in 25 dioxane (5.0 mL) was added to a mixture of appropriate piperazine (1.53 mmol) in dioxane (2.0 mL) and NaHCO 3 (0.26 g, 3.06 mmol) in water (3.0 mL) (in the case of piperazine hydrochlorides the amount of NaHCO 3 was increased by 1 eq), and the resultant solution was stirred at room temperature until initial compounds disappeared (1 2 hours). Water was added to the reaction mixture. In the case of a precipitate formation, 30 it was filtered, washed with water, ether, and dried to give the corresponding methyl (E)-3 (3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4). Otherwise, the reaction mixture was extracted with ethyl acetate, washed successively with water, brine, dried (Na 2 SO4), and solvent removed to give the corresponding methyl (E)-3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4). 35 WO 03/082288 PCT/GB03/01463 - 124 Example 4 Methyl (E)-3-(3-{[4-phenyl-1l-piperazinyl]sulfonyl}phenyl)-2-propenoate (4a) The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester 5 (3) and 1-phenylpiperazine, using Method A, yield 84%. 1 H NMR (DMSO-d, HMDSO), 5: 2.94-3.39 (8H, m); 3.74 (3H, s); 6.65-7.03 (4H, m); 7.05-7.32 (2H, m); 7.60-7.92 (3H, m); 7.94-8.20 (2H, m). Example 5 10 Methyl (E)-3-(3-{[4-benzhydryl -1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4b) The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-benzhydrylpiperazine, using Method A, yield 96%. 'H NMR (DMSO-d 6 , HMDSO), 6: 2.16-2.60 (4H, m); 2.78-3.07 (4H, m); 3.78 (3H, s); 4.32 (1H, s); 6.73 (1H, d, 15 J=16.0 Hz); 7.12-8.27 ppm (15H, m). Example 6 Methyl (E)-3-(3-{[4-(2-methoxyphenyl) -1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4c) 20 The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-(2-methoxyphenyl)-piperazine hydrochloride, using Method A, yield 87%. 1 H NMR (CDCI3, HMDSO), 6: 3.03-3.29 (8H, m); 3.78 (3H, s); 3.83 (3H, s); 6.48 (1H, d, J=16.0 Hz); 6.76-7.07 (4H, m); 7.42-7.94 (4H, m); 7.72 ppm (1H, d, J=16.0 Hz). 25 Example 7 Methyl (E)-3-(3-{[4-(2-chlorophenyl) -1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4d) The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-(2-chlorophenyl)-piperazine hydrochloride, using Method A, yield 81%. 1 H NMR 30 (CDCi3, HMDSO), 6: 2.94-3.38 (8H, m); 3.85 (3H, s); 6.54 (1H, d, J=16.0 Hz); 6.87-7.43 (3H, m); 7.12 (1H, d, J=16.0 Hz); 7.42-7.94 ppm (5H, m).
WO 03/082288 PCT/GB03/01463 -125 Example 8 Methyl (E)-3-(3-{[4-(3-chlorophenyl) -1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4e) The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester 5 (3) and 1-(3-chlorophenyl)-piperazine hydrochloride, using Method A, yield 71%.
1 H NMR
(CDCI
3 , HMDSO), 6:2.94 -3.45 (8H, m); 3.83 (3H, s); 6.56 (1H, d, J=16.0 Hz); 6.60-6.98 (3H, m); 7.16 (1H, d, J=16.0 Hz).; 7.45-8.05 ppm (5H, m). Example 9 10 Methyl (E)-3-(3-{[4-(2-pyridinyl)-l-piperazinyl]sulfonyl}phenyl)-2-propenoate (4f) The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-(2-pyridyl)piperazine, using Method A, yield 82%. 1 H NMR (CDCI 3 , HMDSO), 6: 2.94 -3.25 (4H, m); 3.43-3.72 (4H, m); 3.78 (3H, s); 6.49 (1H, d, J=16.0 Hz); 6.47-6.72 15 (2H, m); 7.27-7.94 (6H, m); 8.00-8.20 ppm (1H, m). Example 10 Methyl (E)-3-(3-{[4-(4-acetylphenyl)-1l-piperazinyl]sulfonyl}phenyl)-2-propenoate (49g) 20 The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 4'-piperazinoacetophenone, using Method A, yield 90%. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.45 (3H, s); 2.94 -3.25 (4H, m); 3.32-3.65 (4H, m, overlapped with a signal of water); 3.78 (3H, s); 6.85 (1H, d, J=16.0 Hz); 6.86-7.16 (2H, m); 7.65-7.96 (5H, m); 8.05-8.27 ppm (2H, m). 25 Example 11 Methyl (E)-3-[3-({4-[4-(dimethylamino)phenethyl]-1l-piperazinyl}sulfonyl)phenyl]-2 propenoate (4h) 30 The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-(4-dimethylaminophenetyl)piperazine, using Method A, yield 91%. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.14-2.63 (8H, m, overlapped with a signal of DMSO); 2.80 (6H, s); 2.81-3.05 (4H, mn); 3.78 (3H, s); 6.63 (2H, d, J=9.4 Hz); 6.84 (1H, d, J=16.0 Hz); 7.00 (2H, d, J=9.4 Hz); 7.61-7.88 (2H, m); 7.83 (1H, d, J=16.0 Hz); 7.99-8.28 ppm (2H, m). 35 WO 03/082288 PCT/GB03/01463 - 126 Example 12 Methyl (E)-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate (41) 5 The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-[2-(1-naphthyloxy)ethyl]piperazine, using Method A, yield 78%. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.36-2.77 (8H, m, overlapped with a signal of DMSO); 2.78-3.09 (4H, m); 3.72 (3H, s); 6.76 (1H, d, J=15.7 Hz); 7.20-7.53 (3H, m); 7.54-7.94 (7H, m); 7.96 8.20 ppm (2H, m). 10 Example 13 Methyl (E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoate (41) 15 The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-[2-(2-naphthyloxy)ethyl]piperazine, using Method A, yield 94%. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.38 -2.65 (6H, m, overlapped with a signal of DMSO); 2.76 (2H, t, J=5.0 Hz); 2.83-3.05 (2H, m); 3.71 (3H, s); 4.11(2H, t, J=5.3 Hz); 6.76 (1H, d, J=16.0 Hz); 6.98-7.56 (4H, m); 7.60-7.92 (6H, m); 7.93-8.18 ppm (2H, mn). 20 Example 14 Methyl (E)-3-(3-{[4-(3,4-dichlorophenyl)-1l-piperazinyl]sulfonyl}phenyl)-2-propenoate (4k) The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester 25 (3) and 1-(3,4-dichlorophenyl)-piperazine, using Method A, yield 85%. 'H NMR (DMSO-d, HMDSO), 6: 2.76-3.12 (4H, m); 3.13-3.38 (4H, m, overlapped with a signal of water); 3.66 (3H, s); 6.76 (1H, d, J=15.9 Hz); 6.87 (1H, dd, J=2.8 and 8.4 Hz); 7.10 (1H, d, J=2.8 Hz); 7.38 (1H, d, J=8.4 Hz); 7.78(1H, d, J=15.9 Hz); 7.60-7.93 (2H, m); 7.95-8.27 ppm (2H, m). 30 Example 15 Methyl (E)-3-(3-{[4-(4-chlorophenyl)-l-piperazinyl]sulfonyl}phenyl)-2-propenoate (41) The title compound was obtained from 3-(3-chlorosulfonylphenyl) acrylic acid methyl ester (3) and 1-(4-chlorophenyl)-piperazine, using Method A, yield 84%. 'H NMR (DMSO-d 6 , 35 HMDSO), 5: 2.76-3.34. (8H, m); 3.72 (3H, s); 6.80 (1H, d, J=15.9 Hz); 6.92 (2H, d, J=8.9 WO 03/082288 PCT/GB03/01463 - 127 Hz); 7.23 (2H, d, J=8.9 Hz); 7.80(1 H, d, J=15.9 Hz); 7.56-7.96 (2H, m); 7.98-8.25 ppm (2H, m). Method B - General Synthesis of (E)-3-(3-f{[4-substituted 1-piperazinyllsulfonyl}phenyl)-2 5 propenoic acids (5a-I) To a suspension or solution of appropriate methyl (E)-3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoate (4a-1) (1.29 mmol) in methanol tetrahydrofuran (2:3) mixture (5.0 mL), 1N NaOH solution (3.87 mL, 3.87 mmol) was 10 added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 1 N KH 2
PO
4 solution. In the case of a precipitate formation, it was filtered, washed with water, ether (or other suitable solvent), and dried to give the corresponding (E)-3-(3-([4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5). 15 Otherwise, the reaction mixture was extracted with ethyl acetate, washed successively with water, brine, dried (Na 2
SO
4 ), and solvent removed to give the corresponding (E)-3-(3 {[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5). Example 16 20 (E)-3-(3-{[4-Phenyl-1l-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (Sa) The title compound was obtained from methyl (E)-3-(3-{[4-phenyl-1 piperazinyl]sulfonyl}phenyl)-2-propenoate (4a) as a white solid, using Method B, yield 61%. 'H NMR (DMSO-d 6 , HMDSO), 5: 2.87-3.65 (8H, m); 6.54-6.98 (4H, m); 7.00-7.36 25 (2H, m); 7.58-7.92 (3H, m); 7.94-8.23 (2H, m). Example 17 (E)-3-(3-{[4-Benzhydryl-1 -piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5b) 30 The title compound was obtained from methyl (E)-3-(3-{[4-benzhydryl-1 piperazinyl]sulfonyl}phenyl)-2-propenoate (4b) as a white solid, using Method B, yield 70%. 1H NMR (DMSO-d 6 , HMDSO), 5: 2.20-2.56 (4H, m); 2.80-3.07 (4H, m); 4.27 (1H, s); 6.67 (1H, d, J=16.0 Hz); 7.05-8.16 ppm (15H, m).
WO 03/082288 PCT/GB03/01463 - 128 Example 18 (E)-3-(3-{[4-(2-Methoxyphenyl)-1l-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5_c) The title compound was obtained from methyl (E)-3-(3-{[4-(2-methoxyphenyl)-1 5 piperazinyl]sulfonyl}phenyl)-2-propenoate (4c) as a white solid, using Method B, yield 84%. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.76-3.25 (8H, m); 3.72 (3H, s); 6.74 (1H, d, J=16.0 Hz); 6.76-7.14 (4H, m); 7.60-7.94 (2H, m); 7.76 (1H, d, J= 16.0 Hz); 7.94-8.27 ppm (2H, m). 10 Example 19 (E)-3-(3-{[4-(2-Chlorophenyl)-l-piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5d) The title compound was obtained from methyl (E)-3-(3-{[4-(2-chlorophenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoate (4d), using Method B, yield 83%. 1 H NMR 15 (DMSO-d6, HMDSO), 6: 2.72-3.27 (8H, m); 6.72 (1H, d, J=16.0 Hz); 6.89-7.52 (4H, m); 7.60-7.92 (2H, m); 7.74 (1H, d, J= 16.0 Hz); 7.96-8.25 ppm (2H, m). Example 20 (E)-3-(3-{[4-(3-Chlorophenyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenoic acid (Se) 20 The title compound was obtained from methyl (E)-3-(3-{[4-(3-chlorophenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoate (4e), using Method B, yield 89%. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.87 -3.16 (6H, m); 3.17-3.67 (2H, m, overlapped with a signal DMSO); 6.67 (1H, d, J=16.0 Hz); 6.68-7.00 (3H, m); 7.02-7.34 (1H, m); 7.56-7.87 (2H, m); 25 7.72 (1H, d, J= 16.0 Hz); 7.94-8.23 ppm (2H, m). Example 21 (E)-3-(3-{[4-(2-Pyridinyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5f) 30 The title compound was obtained from methyl (E)-3-(3-{[4-(2-pyridinyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoate (4f), using Method B, yield 91%. 1 H NMR (DMSO-do, HMDSO), 6: 2.83 -3.14 (4H, m); 3.43-3.69 (4H, m); 6.52-6.89 (2H, m); 6.67 (1H, d, J=16.0 Hz); 7.36-7.83 (3H, m); 7.69 (1H, d, J= 16.0 Hz); 7.94-8.18 ppm (3H, m).
WO 03/082288 PCT/GB03/01463 - 129 Example 22 (E)-3-(3-{[4-(4-Acetylphenyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5g) The title compound was obtained from methyl (E)-3-(3-{[4-(4-acetylphenyl)-1 5 piperazinyl]sulfonyl}phenyl)-2-propenoate (4g), using Method B, yield 85%. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.38 (3H, s); 2.89 -3.20. (4H, m); 3.21-3.67 (4H, m, overlapped with a signal of water); 6.69 (1H, d, J=16.0 Hz); 6.70-7.11 (2H, m); 7.53-7.94 (5H, m); 7.96-8.20 ppm (2H, m). 10 Example 23 (E)-3-[3-({4-[4-(Dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (5h) The title compound was obtained from methyl (E)-3-[3-({4-[4-(dimethylamino)phenethyl] 15 1-piperazinyl}sulfonyl)phenyl]-2-propenoate (4h), using Method B, yield 80%. 1 H NMR (DMSO-d 6 , HMDSO), 5:2.23-2.67 (8H, m, overlapped with a signal of DMSO); 2.80 (6H, s); 2.72-3.09 (4H, m); 6.63 (2H, d, J=8.0 Hz); 6.74 (1H, d, J=16.0 Hz); 6.99 (2H, d, J=8.0 Hz); 7.51 -7.89 (3H, m); 7.90-8.32 ppm (2H, m). 20 Example 24 (E)-3-[3-({4-[2-(1-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (5i) The title compound was obtained from methyl (E)-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoate (41), using Method B, yield 90%. 'H NMR 25 (DMSO-d 6 , HMDSO), 65: 2.36-2.76 (6H, m, overlapped with a signal of DMSO); 2.78-3.07 (6H, m); 6.69 (1H, d, J= 15.7 Hz); 7.22-7.56 (3H, m); 7.58-7.92 (7H, m); 7.93-8.16 ppm (2H, m). Example 25 30 (E)-3-[3-({4-[2-(2-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (5j) The title compound was obtained from methyl (E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoate (4j), using Method B, yield 84%. 1 H NMR (DMSO-d6, HMDSO), 5: 2.36 -2.58 (6H, m, overlapped with a signal of DMSO); 2.76 (2H, 35 t, J=5.0 Hz); 2.82-3.05 (2H, m); 4.11(2H, t, J=5.3 Hz); 6.67(1H, d, J= 16.0 Hz); 6.98-7.52 (4H, m); 7.53-7.87 (6H, m); 7.88-8.16 ppm (2H, mn).
WO 03/082288 PCT/GB03/01463 - 130 Example 26 (E)-3-(3-{[4-(3,4-Dichlorophenyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5k) 5 The title compound was obtained from methyl (E)-3-(3-{[4-(3,4-dichlorophenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoate (4k), using Method B, yield 87%. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.69 -3.16 (4H, m); 3.17-3.47 (4H, m); 6.69 (1H, d, J=16.0 Hz); 6.92 (1H, dd, J=2.8 and 8.4 Hz); 7.13 (1H, d, J=2.8 Hz); 7.38 (1H, d, J=8.4 Hz); 7.54 (1H, d, J=16.0 Hz); 7.58-7.92 (2H, m); 7.93-8.18 ppm (2H, m). 10 Example 27 (E)-3-(3-{[4-(4-Chlorophenyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenoic acid (51) The title compound was obtained from methyl (E)-3-(3-{[4-(4-chlorophenyl)-l 15 piperazinyl]sulfonyl}phenyl)-2-propenoate (41), using Method B, yield 75%. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.83-3.49 (8H, m, overlapped with a signal of water); 6.67 (1H, d, J=15.9 Hz); 6.89 (1H, d, J= 8.9 Hz); 7.18 (2H, d, J=8.9 Hz); 7.49-7.87 (2H, m); 7.69 (1H, d, J=15.9 Hz); 7.88-8.20 ppm (2H, m). 20 Method C - General Synthesis of (E)-3-(3-f{[4-substituted 1-piperazinyllsulfonyl}phenyl)-2 propenoyl chlorides (6a-I) To a suspension of appropriate (E)-3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2 propenoic acid (5a-1) (0.78 mmol) in dichloromethane (4.0 mL) oxalyl chloride (0.21 mL, 25 2.37 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 4000 for one hour and concentrated under reduced pressure to give crude (E)-3 (3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6). Example 28 30 (E)-3-(3-{[4-Phenyl-1l-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6a) The title compound was obtained from (E)-3-(3-{[4-phenyl-1l-piperazinyl]sulfonyl}phenyl) 2-propenoic acid (Sa), using Method C, in a form of a crude product.
WO 03/082288 PCT/GB03/01463 - 131 Example 29 (E)-3-(3-{[4-Benzhydryl-1l-piperazinyl]sulfonyl}phenyl)-2-propenoy chloride (6b) The title compound was obtained from (E)-3-(3-{[4-benzhydryl-1 5 piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5b), using Method C, in a form of a crude product. Example 30 (E)-3-(3-{[4-(2-Methoxyphenyl)-1l-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6c) 10 The title compound was obtained from (E)-3-(3-{[4-(2-methoxyphenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5c), using Method C, in a form of a crude product. 15 Example 31 (E)-3-(3-{[4-(2-Chlorophenyl)-1l-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6d) The title compound was obtained from (E)-3-(3-{[4-(2-chlorophenyl)-l piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5d), using Method C, in a form of a crude 20 product. Example 32 (E)-3-(3-{[4-(3-Chlorophenyl)-1l-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6e) 25 The title compound was obtained from (E)-3-(3-{[4-(3-chlorophenyl)-l piperazinyl]sulfonyl}phenyl)-2-propenoic acid (se), using Method C, in a form of a crude product. Example 33 30 (E)-3-(3-{[4-(2-Pyridinyl)-1l-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6f) The title compound was obtained from (E)-3-(3-{[4-(2-pyridinyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5f), using Method C, in a form of a crude product. 35 WO 03/082288 PCT/GB03/01463 - 132 Example 34 (E)-3-[3-({4-[4-(1-Chlorovinyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoy chloride (6g) 5 The title compound was obtained from (E)-3-(3-{[4-(4-acetylphenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5g), using Method C, in a form of a crude product. Example 35 10 (E)-3-[3-({4-[4-(Dimethylamino)phenethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (61h) The title compound was obtained from (E)-3-[3-({4-[4-(dimethylamino)phenethyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoic acid (§h), using Method C, in a form of a crude 15 product. Example 36 (E)-3-[3-({4-[2-(1-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyI)phenyl]-2-propenoyl chloride (6i) 20 The title compound was obtained from (E)-3-[3-({4-[2-(1 -naphthyloxy)ethyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoic acid (5i), using Method C, in a form of a crude product. 25 Example 37 (E)-3-[3-({4-[2-(2-Naphthyloxy)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (6j) The title compound was obtained from (E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1 30 piperazinyl}sulfonyl)phenyl]-2-propenoic acid (Sj), using Method C, in a form of a crude product.
WO 03/082288 PCT/GB03/01463 -133 Example 38 (E)-3-(3-{[4-(3,4-Dichlorophenyl)-l-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6k) The title compound was obtained from (E)-3-(3-{[4-(3,4-dichlorophenyl)-1 5 piperazinyl]sulfonyl}phenyl)-2-propenoic acid (5k), using Method C, in a form of a crude product. Example 39 (E)-3-(3-{[4-(4-Chlorophenyl)-l-piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (61) 10 The title compound was obtained from (E)-3-(3-{[4-(4-chlorophenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoic acid (51), using Method C, in a form of a crude product. 15 Method D - General Synthesis of (E)-N-hydroxy-3-(3-{[4-substituted 1 piperazinyllsulfonyl}phenvl)-2-propenamides To a suspension of hydroxylamine hydrochloride (0.27 g, 3.90 mmol) in tetrahydrofuran (6.0 mL) a saturated NaHCO solution (6.9 mL) was added and the resultant mixture was 20 stirred at ambient temperature for 10 minutes. To the reaction mixture an appropriate (E) 3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)- 2 -propenoyl chloride (6a-1) (ca. 0.78 mmol) solution in tetrahydrofuran (4.0 mL) was added and the obtained mixture was stirred at ambient temperature for ca. one hour. The organic layer was separated, the water layer was supplemented with water (ca. 5 mL) and extracted with ethyl acetate. 25 The organic extracts were combined, washed successively with water, brine, and dried (Na 2
SO
4 ). The solvent was removed and the crude product was washed with an appropriate solvent (ether, methanol, ethyl acetate, acetonitrile etc.) or crystallized from ether, methanol, ethyl acetate or acetonitrile, or their mixtures to give the corresponding target (E)-N-hydroxy-3-(3-{[4-substituted 1-piperazinyl]sulfonyl}phenyl)-2-propenamide. 30 Otherwise, the crude reaction product was chromatographed on silica gel with chloroform - methanol as eluents to give the corresponding (E)-N-hydroxy-3-(3-{[4-substituted 1 piperazinyl]sulfonyl}phenyl)-2-propenamide.
WO 03/082288 PCT/GB03/01463 -134 Example 40 (E)-N-Hydroxy-3-{3-[(4-phenyl-1l-piperazinyl)sulfonyl]phenyl}-2-propenamide (PX118490) The title compound was obtained from (E)-3-(3-{[4-phenyl-l1-piperazinyl]sulfonyl}phenyl) 5 2-propenoyl chloride (6a) as white crystals, using Method D, yield 73% (on 5a). M.p. 201 C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.91-3.39 (8H, m, overlapped with a signal of water); 6.62 (1H, d, J=16.0 Hz); 6.74-6.99 (3H, m); 7.06-7.34 (2H, m); 7.57 (1H, d, J=16.0 Hz); 7.56-8.12 (4H, m); 9.11 (1H, brs); 10.79 (1H, s). HPLC analysis on Zorbax SB-C 1 8 column: impurities 1.3% (column size 4.6x150 mm; mobile phase acetonitrile - 0.1% 10 H 3
PO
4 , gradient from 50:50 to 100:0; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min.; detector: UV 254 nm). Anal. Calcd for C 19
H
21
N
3 0 4 S,%: C 58.90, H 5.46, N 10.84. Found,%: C 58.73, H 5.34, N 10.69. Example 41 15 (E)-N-Hydroxy-3-{3-[(4-benzhydryl-1l-piperazinyl)sulfonyl]phenyl}-2-propenamide (PX118491) The title compound was obtained from (E)-3-(3-{[4-benzhydryl-1 piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6b) as white crystals, using Method D, 20 yield 57% (on 5b). M.p. 1560C. 1 H NMR (DMSO-de, HMDSO), 6: 2.18-2.54 (4H, m, overlapped with a signal of DMSO); 2.75-3.11 (4H, m); 4.31 (1H, s); 6.64 (1 H, d, J=16.0 Hz); 7.01-8.11 (15H, m); 9.15 (1 H, br s); 10.83 (1H, s). HPLC analysis on Symmetry C 1 8 column: impurities 7% (column size 3.9x150 mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), 50:50; sample concentration 1 mg/ml; flow rate 0.75 mL/min.; 25 detector UV 220 nm). Anal. Calcd for C 2 6H 27
N
3 0 4 S * 0.7 H 2 0,%: C 63.71, H 5.84, N 8.57. Found,%: C 63.81, H 5.77, N 8.34. Example 42 (E)-N-Hydroxy-3-{3-[(4-(2-methoxyphenyl)-1-piperazinyl)sulfonyl]phenyl}-2-propenamide 30 (PX118810) The title compound was obtained from (E)-3-(3-{[4-(2-methoxyphenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride ( c) as white crystals, using Method D, yield 59% (on 5c). M.p. 190°C. 'H NMR (DMSO-d 6 , HMDSO), 6: 2.72-3.25 (8H, m); 3.67 35 (3H, s); 6.65 (1H, d, J=16.0 Hz); 6.76-7.12 (4H, m); 7.61 (1H, d, J=16.0 Hz); 7.60-8.07 (4H, m); 9.09 (1H, br s); 10.78 (1H, s). HPLC analysis on Zorbax SB C 1 8 column: WO 03/082288 PCT/GB03/01463 -135 impurities 2% (column size 4.6x150 mm; mobile phase acetonitrile- 0.1% H 3
PO
4 , 50:50 10 min, 100:0 5 min; sample concentration 1 mg/ml; flow rate 1.5 mL/min.; detector UV 254 nm). Anal. Calcd for C 20
H
23
N
3 0sS,%: C 57.54, H 5.55, N 10.06. Found,%: C 57.26, H 5.46, N 9.99. 5 Example 43 (E)-N-Hydroxy-3-{3-[(4-(2-chlorophenyl)-1-piperazinyl)sulfonyl]phenyl}-2-propenamide (PX118811) 10 The title compound was obtained from (E)-3-(3-{[4-(2-chlorophenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6d), using Method D, yield 84% (on 5d). M.p. 1830C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.76-3.32 (8H, m); 6.63 (1H, d, J=16.0 Hz); 6.92-7.48 (4H, m); 7.59 (1H, d, J=16.0 Hz); 7.58-8.12 (4H, m); 9.12 (1H, brs); 10.80 (1H, s). HPLC analysis on Zorbax SB C18 column: impurities 2% (column size 4.6x150 mm; 15 mobile phase acetonitrile- 0.1% H 3
PO
4 , 50:50 10 min, 100:0 5 min; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min; detector: UV 254 nm). Anal. Calcd for C 19
H
20
CIN
3 0 4 S,%: C 54.09, H 4.78, N 9.96. Found,%: C 53.99, H 4.73, N 9.80. Example 44 20 (E)-N-Hydroxy-3-{3-[(4-(3-chlorophenyl)-1 -piperazinyl)sulfonyl]phenyl}-2-propenamide (PX118812) The title compound was obtained from (E)-3-(3-{[4-(3-chlorophenyl)-l piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6e), using Method D, yield 75% (on 5e). 25 M.p. 2010C. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.83-3.45 (8H, m); 6.63 (1H, d, J=16.0 Hz); 6.68-7.02 (3H, m); 7.16 (1H, t, J=7.8 Hz); 7.58 (1H, d, J=16.0 Hz); 7.60-8.07 (4H, m); 9.16 (1H, br s); 10.72 (1 H, s). HPLC analysis on Symmetry C8 column: impurities 3.3% (column size 3.9x150 mm; mobile phase acetonitrile- 0.1M phosphate buffer (pH 2.5), 45:55; sample concentration 0.5 mg/ml; flow rate 1.4 mL/min; detector UV 254 nm). Anal. Calcd 30 for C 19
H
20
CIN
3 0 4 S, containing 4% of inorganic impurities,%: C 51.93, H 4.59, N 9.56. Found,%: C 52.00, H 4.59, N 9.39.
WO 03/082288 PCT/GB03/01463 - 136 Example 45 (E)-N-Hydroxy-3-{3-[(4-(2-pyridinyl)-1-piperazinyl)sulfonyl]phenyl}-2-propenamide (PX118807) 5 The title compound was obtained from (E)-3-(3-{[4-(2-pyridinyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6f), using Method D, yield 63% (on 5f). M.p. 1120C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.78-3.18 (4H, mn); 3.41-3.76 (4H, m); 6.45 6.91 (3H, m); 7.38-8.19 (7H, m); 9.13 (1H, brs); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 4% (column size 3.9x150 mm; mobile phase acetonitrile 10 0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min; detector UV 254 nm). Anal. Calcd for C 1 8
H
20
N
4 0 4 S * H 2 0, containing 1.5% of inorganic impurities,%: C 52.39, H 5.37, N 13.58. Found,%: C 52.45, H 5.23, N 13.39. Example 46 15 (E)-3-[3-({4-[4-(1 -Chlorovinyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-N-hydroxy-2 propenamide (PX118933) The title compound was obtained from (E)-3-[3-({4-[4-(1-chlorovinyl)phenyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (6g), using Method D, yield 24% (on 5g). 20 M.p. 2030C (dec.). TLC: single spot at Rf 0.3 (ethyl acetate-methanol, 4:1; detection - UV 254 nm). 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.94-3.20 (4H, m); 3.21-3.63 (4H, m, overlapped with a signal of water); 5.38 (1H, d, J= 4.0 Hz); 5.83 (1H, d, J= 4.0 Hz); 6.63 (1H, d, J=16.0 Hz); 6.93 (2H, d, J=9,0 Hz); 7.54 (2H, d, J= 9.0 Hz); 7.60 (1H, d, J=16.0 Hz); 7.43-8.05 (4H, m); 9.16 (1H, br s); 10.85 ppm (1H, br s). Anal. Calcd for 25 C21H 22
CIN
3 0 4 S, containing 1.9% of inorganic material,%: C 55.24, H 4.86, N 9.20. Found,%: C 55.22, H 4.78, N 9.45. Example 47 (E)-3-[3-({4-[4-(Dimethylamino)phenethyl]-1-piperazinyl)sulfonyl)phenyll-N-hydroxy-2 30 propenamide (PX1 18951) The title compound was obtained from (E)-3-[3-({4-[4-(dimethylamino)phenethyl]-l piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (6h), using Method D, yield 17% (on 5h). M.p. 1890C. 'H NMR (DMSO-d 5 , HMDSO), 5: 2.36-2.57 (8H, m, overlapped with a signal 35 of DMSO); 2.80 (6H, s); 2.83-2.94 (4H, m); 6.60 (2H, d, J=8.0 Hz); 6.61 (1H, d, J=15.7 Hz); 6.96 (2H, d, J=8.0 Hz); 7.57 (1H, d, J=15.7 Hz); 7.66-7.75 (2H, mn); 7.83-7.97 (2H, WO 03/082288 PCT/GB03/01463 -137 m); 9.17 (1H, br s); 10.83 (1H, br s). HPLC analysis on Alltima C 1 8 column: impurities 3% (column size 4.6x150 mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 15:85; sample concentration 1.0 mg/ml; flow rate 1.0 mL/ min; detector UV 220 nm). Anal. Calcd for C 2 3
H
30
N
4 0 4 S,%: C 60.24, H 6.59, N 12.22. Found,%: C 60.05, H 6.52, N 12.16. 5 Example 48 (E)-N-Hydroxy-3-[3-({4-[2-(1 -naphthyloxy)ethyl]- 1-piperazinyl}-sulfonyl)phenyl]-2 propenamide (PXI 18934) 10 The title compound was obtained from (E)-3-[3-({4-[2-(1-naphthyloxy)ethyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (61), using Method D, yield 68% (on 15i). M.p. 1780C. 1 H NMR (DMSO-ds, HMDSO), 65: 2.41-2.68 (6H, m, overlapped with a signal of DMSO); 2.75-3.00 (6H, m); 6.61 (1H, d, J=16.0 Hz); 7.34 (1H, d, J= 8.4 Hz); 7.39-7.52 (2H, m); 7.57 (1H, d, J=16.0 Hz); 7.63-7.97 (8H, m); 9.17 (1H, brs); 10.84 ppm (1H, brs). 15 HPLC analysis on Omnispher C18 column: impurities 2.2% (column size 4.6x150 mm; mobile phase acetonitrile - 0.2 M acetate buffer (pH 5.0), 40:60; sample concentration 0.5 mg/ml; flow rate 1.5 mL/ min; detector UV 230 nm). Anal. Calcd for C 25
H
27
N
3 0 5 S,%: C 62.35, H 5.65, N 8.73. Found,%: C 62.42, H 5.56, N 8.69. 20 Example 49 (E)-N-Hydroxy-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1 -piperazinyl}-sulfonyl)phenyl]-2 propenamide (PX118935) The title compound was obtained from (E)-3-[3-({4-[2-(2-naphthyloxy)ethyl]-1 25 piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (gi), using Method D, yield 57% (on 5). M.p. 1300C. 'H NMR (DMSO-d 6 , HMDSO), 6: 2.54-2.68 (4H, m, overlapped with a signal of DMSO); 2.76 (2H, t, J=5.0 Hz); 2.82-3.03 (4H, m); 4.12 (2H, t, J=5.3 Hz); 6.60 (1H, d, J=16.0 Hz); 7.10 (1H, dd, J=8.9 and 2.0 Hz); 7.28 (1H, d, J=2.0 Hz); 7.31 (1H, t, J=7.9 Hz); 7.43 (1H, t, J=7.6 Hz); 7.55 (1 H, d, J=16.0 Hz); 7.62-7.95 (7H, m); 9.19 (1H, br s); 30 10.82 ppm (1 H, br s). HPLC analysis on Omnispher C18 column: impurities 3.3% (column size 4.6x150 mm; mobile phase acetonitrile - 0.2 M acetate buffer (pH 5.0), 40:60; sample concentration 0.25 mg/ml; flow rate 1.5 mL/ min; detector UV 230 nm). Anal. Calcd for
C
25
H
27
N
3 0 5 S, containing 6% of inorganic impurities,%: C 58.61, H 5.31, N 8.20. Found,%: C 58.63, H 5.33, N 8.01. 35 WO 03/082288 PCT/GB03/01463 -138 Example 50 (E)-3-(3-{[4-(3,4-Dichlorophenyl)-1-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide (PX118971) 5 The title compound was obtained from (E)-3-(3-{[4-(3,4-dichlorophenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (6k), using Method D, yield 71% (on 5k). M.p. 193 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.89-3.09 (4H, m); 3.18-3.33 (4H, m, overlapped with a signal of water); 6.61 (1H, d, J=15.9 Hz); 6.89 (1H, dd, J=2.8 and 8.4 Hz); 7.11 (1H, d, J=2.8 Hz); 7.38 (1H, d, J=8.4 Hz); 7.57 (1H, d, J=15.9 Hz); 7.66-7.82 10 (2H, m); 7.87-8.00 (2H, m); 9.16 (1H, s); 10.82 (1H, s). HPLC analysis on Omnispher C18 column: impurities 3.3% (column size 4.6x150 mm; mobile phase acetonitrile - 0.2 M acetate buffer (pH 5.0), 50:50; sample concentration 0.5 mg/ml; flow rate 1.3 mL/ min; detector UV 254 nm). Anal. Calcd for C 1
,H
19 C1 2
N
3 0 4 S,%: C 50.01, H 4.20, N 9.21. Found,%: C 49.94, H 4.06, N 9.10. 15 Example 51 (E)-3-(3-{[4-(4-Chlorophenyl)- 1 -piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide (PX1 18972) 20 The title compound was obtained from (E)-3-(3-{[4-(4-chlorophenyl)-1 piperazinyl]sulfonyl}phenyl)-2-propenoyl chloride (61), using Method D, yield 79% (on 51). M.p. 2150C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.89-3.12 (4H, m); 3.12-3.27 (4H, m); 6.61 (1H, d, J=15.9 Hz); 6.91 (2H, d, J=8.9 Hz); 7.21 (2H, d, J=8.9 Hz); 7.57 (1H, d, J=15.9 Hz); 7.67-7.85 (2H, m); 7.86-8.05 (2H, m); 9.26 (1H, br s); 10.65 (1H, br s). HPLC 25 analysis on Alltima C 18 column: impurities <1% (column size 4.6x150 mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 1.5 mL/ min; detector UV 254 nm). Anal. Calcd for C 19
H
20 ClN 3 0 4 S,%: C 54.09, H 4.78, N 9.96. Found,%: C 54.08, H 4.62, N 9.90. 30 Example 52 (E)-N-Hydroxy-3-[3-({4-[(E)-3-phenyl-2-propenyl]-1-piperazinyl)-sulfonyl)phenyl]-2 propenamide (PX1 18870) The title compound was obtained using methods analogous to those described above. 35 M.p. 178 0 C. 'H NMR (DMSO-dG, TMS) 65: 2.60-3.49 (8 H, m, partly overlapped with a signal of water), 3.09 (2H, d, J=6.0 Hz); 6.13 (IH, dt, J= 16.0 and 6.0 Hz), 6.49 (IH, d, J= WO 03/082288 PCT/GB03/01463 -139 16.0 Hz); 6.60 (1H, d, J=16.0 Hz); 7.16- 7.56 (5H, m); 7.57-8.00 (5H, m); 9.20 (IH, br s); 10.78 ppm (IH, br s). HPLC analysis on an Omnispher 5 C 18 column: impurities 1.0 % (column size: 4.6x150 mm - mobile phase: acetonitrile -0.1 M phosphate buffer (pH 2.5), 25:75; sample concentration 0.16 mg/ml; flow rate: 1.3 mL/min; detector UV 254 nm). 5 Anal.Calcd. for C 22
H
23
N
3 0 4 S, %: C 61.81, H 5.89, N 9.83. Found, % C 61.43, H 5.84, N 9.65. Example 53 (E)-N-Hydroxy-3-(3-{[4-(4-methoxyphenyl)-1-piperazinyl]-sulfonyl)}phenyl)-2-propenamide 10 (PX118871) The title compound was obtained using methods analogous to those described above. M.p. 203 0 C. 1H NMR (DMSO-de, HMDSO) 5: 2.96-3.12 (8H, m); 3.66 (3H, s); 6.62 (IH, d, J= 15.7 Hz); 6.79 (2H, d, J=9.4 Hz); 6.85 (2H, d, J=9.4 Hz); 7.59 (IH, d, J=15.7 Hz); 7.62 15 7.70 (2H, m); 7.92-8.05 (2H, m); 9.15 (IH, br s); 10.82 ppm (IH, br s). HPLC analysis on an Omnispher 5 C1 8 column: impurities 1.3%. (column size 4.6x150 mm; mobile phase acetonitrile -0.1 M phosphate buffer (pH 2.5), 40:60; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min; detector UV 220 nm). Anal. Calcd. for C 20
H
23
N
3 0sS, %: C 57.54, H 5.55, N 10.06. Found, %: C 57.55, H 5.41, N 9.98. 20 Example 54 (E)-N-hydroxy-3-(3{[4(3-methoxyphenyl)piperazinyl]sulfonyl}phenyl)-2-propenamide (PX1 18872) 25 The title compound was obtained using methods analogous to those described above. M.p. 196 0 C. 'H NMR (DMSO-de, HMDSO) 5: 2.96-3.10 (4 H, m), 3.13-3.26 (4H, m); 3.68 (3H, s); 6.34- 6.52 (3H, m); 6.61 (IH, d, J=15. 7 Hz); 7.08 (IH, t, J=7.9 Hz); 7.57 (IH, d, J=15.7 Hz); 7.64-7.80 (2H, m); 7.89-7.98 (2H, m); 9.15 (IH, br s); 10.81 ppm (IH, br s). HPLC analysis on an AIItima C1 8 column: impurities 3.5% (column size 4.6x150mm; 30 mobile phase acetonitrile -0.1 M phosphate buffer (pH 2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 1.4 mL/min; detector UV 220 nm). Anal. Calcd for C 20
H
23
N
3 0sS, containing 1.5% of inorganic impurities, %: C 56.68, H 5.47, N 9.91. Found, %: C 56.79, H 5.31, N 9.81.
WO 03/082288 PCT/GB03/01463 -140 Example 55 (E)-3-(3-{[4-(1,3-Benzodioxol-5-ylmethyl)-1 -piperazinyl]sulfonyl}-phenyl)-N-hydroxy-2-, propenamide (PXI 18873) 5 The title compound was obtained using methods analogous to those described above. M.p. 1720C. 1 H NMR (DMSO-d 6, HMDSO) 6: 2.32-2.45 (4 H, m), 2.82-2.97 (4H, m); 3.34 (2H, s, overlapped with a signal of water); 5.94 (2H, s); 6.60 (IH, d, J=15. 7 Hz); 6.67 (IH, d, J=7.9 Hz); 6.76 (IH, s); 6.78 (IH, d, J=8.3 Hz); 7.56 (IH, d, J=15. 7 Hz); 7.66- 7.74 (2H, m); 7.83-7.96 (2H, m); 9.14 (IH, brs); 10.80 ppm (IH, brs). HPLC analysis on an 10 Omnispher 5 C18 column : impurities 1.3% (column size 4.6x150 mm; mobile phase acetonitrile -0.1 M phosphate buffer (pH 2.5), 35:65; sample concentration 1.0 mg/ml; flow rate: 1.3 mL/min; detector UV 254 nm). Anal. Calcd. for C21 H 2 3
N
3 0 6 S, %: C 56.62, H 5.20, N 9.43. Found, %: C 56.35, H 5.02, N 9.24. 15 Example 56 (E)-3-{3-[(4-Benzyl-l-piperazinyl)sulfonyl]phenyl}-N-hydroxy-2-propenamide (PX1 18874) The title compound was obtained using methods analogous to those described above. 20 M.p 1850C. 1 H NMR (DMSO-d 6 , HMDSO) 5:2.42 (4H, m), 2.91 (4H, m); 3.45 (2H, s); 6.59 (IH, d, J= 15.7 Hz); 7.15-7.31 (5H, m); 7.56 (IH, d, J=15.7 Hz); 7.62-7.76 (2H, m); 7.81 7.98 (2H, m); 9.14 (IH, br s); 10.80 ppm (IH, br s). HPLC analysis on an Omnispher 5 C18 column: impurities 2.3% (column size 4.6x150 mm; mobile phase acetonitrile-0.1 M phosphate buffer (pH 2.5), 40:60; sample concentration 0.33 mg/ml; flow rate 1.3 mL/min; 25 detector UV 220 nm). Anal Calcd. for C 20
H
23
N
3 0 4 S, %: C 59.83, H 5.77, N 10.47. Found, %: C 59.67, H 5.62, N 10.34. Example 57 (E)-3-[3-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-N-hydroxy-2 30 propenamide (PX1 18875) The title compound was obtained using methods analogous to those described above. M.p. foam. 1 H NMR (DMSO-d 6 , HMDSO) 5: 2.18-2.45 (4H, m), 2.78-3.09 (4H, m); 4.36 (IH, s); 6.58 (IH, d,J= 16.0 Hz); 6.89-7.20 (4H, m); 7.22-7.58 (5H, m); 7.60-8.05 (4H, m); 35 9.98 ppm (2H, br s). HPLC analysis on an Alltima C18 column: impurities 6.5% (column size 4.6x150mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 60:40; WO 03/082288 PCT/GB03/01463 - 141 sample concentration 0.5 mg/ml; flow rate 1.5 mL/min; detector: UV 220 nm). Anal Calcd. for C 26
H
25
F
2
N
3 0 4 S , %: C 60.31, H 5.24, N 7.54. Found, %: C 60.13, H 5.17, N 7.51. Example 58 5 (E)-N-Hydroxy-3-(3-{[3-methyl-4-(4-methylphenyl)-1-piperazinyl]sulfonyl}phenyl)-2 propenamide (PX1 18876) The title compound was obtained using methods analogous to those described above. M.p. 1860C. 1 H NMR (DMSO-d 6 , HMDSO) 6: 0.94 (3H, d, J=6.4 Hz); 2.20 (3H, s); 2.56 10 2.83 (IH, m, partly overlapped with a signal of water); 2.84-3.67 (5H, m); 3.80-4.16 (IH, m); 6.45-6.78 (4H, m); 6.94-7.20 (IH, m); 7.60 (lH, d, J= 16.0 Hz); 7.69-8.14 (4H, m); 9.98 (2H, br s). HPLC analysis on an AIItima C18 column: impurities 3.0% (column size 4.6xl 50mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 50:50; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector UV 220 nm). Anal. Calcd. for C 21
H
25
N
3 0 4 S * 0.1 15 EtOH, %: C 60.58, H 6.13, N 9.90. Found, %: C 60.46, H 6.05, N 9.84. Example 59 (E)-3-(3-{[4-(2-Fluorophenyl)-I-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide (PX118877) 20 The title compound was obtained using methods analogous to those described above. M.p. 1760C. 1 H NMR (DMSO-d 6 , HMDSO) 6: 2.83-3.15 (8H, m); 6.63 (IH, d, J=16.0 Hz); 6.83- 7.27 (4H, m); 7.60 (IH, d, J= 16.0 Hz); 7.65- 8.05 (4H, m); 9.12 (IH, br s); 10.83 ppm (IH, br s). HPLC analysis on Ultra JBD: impurities 1.0% (column size 4.6x150 mm; mobile 25 phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 60:40; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector UV 230nm). Anal Calcd. for C19H20FN304S, %: C 56.29, H 4.97, N 10.36. Found, %: C 56.25, H 4.89, N 10.16. Example 60 30 (E)-N-Hydroxy-3-[3-({4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2 propenamide (PX118878) The title compound was obtained using methods analogous to those described above. M.p. 1730C. 1 H NMR (DMSO-d 6 , HMDSO) 5: 2.94-3.25 (8H, m); 6.63 (IH, d, J=16.0 Hz); 35 6.98-7.29 (3H, m); 7.39 (IH, d, J=7.6 Hz); 7.69 (IH, d, J=16.0 Hz); 7.60-8.09 (4H, m); 10.05 ppm (2H, br s). HPLC analysis on Alltima CB8: impurities 5.5% (column size 4.6x150 WO 03/082288 PCT/GB03/01463 - 142 mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 50:50; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min; detector UV 220 nm.) Anal. Calcd. for
C
20
H
20
F
3
N
3 0 4 S * 0.1EtOAc, %: C 52.78, H 4.52, N 9.05. Found, %: C 52.74, H 4.36, N 8.88. 5 Example 61 (E)-N-Hydroxy-3-(3-{[4-(3-nitrophenyl)-1-piperazinyl]sulfonyl}phenyl)-2-propenamide (PX118893) 10 The title compound was obtained using methods analogous to those described above. M.p. 162 oC. 1 H NMR (DMSO-d 6 , HMDSO) 6: 2.94-3.20 (4H, m); 3.45-3.69 (4H, m); 6.65 (IH, d, J=16.0 Hz); 7.02 (2H, d, J=9.0 Hz); 7.58 (IH, d, J= 16.0 Hz); 7.62-7.83 (2H, m); 7.84- 8.20 (4H, m); 10.20 (2H, br s). HPLC analysis on Omnisphere 5 C 18 : impurities 2.0% (column size 4.6x150mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 15 40:60; sample concentration 0.3 mg/ml; flow rate 1.5 mL/min; detector UV 220 nm). Anal. Calcd. for C 19
H
20
N
4 0 6 S containing 2.3% inorganic material, %: C 51.56, H 4.55, N 12.66. Found, %: C 51.54, H 4.50, N 12.57. Example 62 20 (E)-N-Hydroxy-3-(3-{[4-(2-pyrimidinyl)-1 -piperazinyl]sulfonyl}-phenyl)-2-propenamide (PX118894) The title compound was obtained using methods analogous to those described above. M.p. 200 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.78-3.15 (4H, m); 3.63-3.94 (4H, m); 6.58 25 (IH, d, J=16.0 Hz); 6.63 (IH, t, J=6.4 Hz); 7.56 (IH, d, J= 16.0 Hz); 7.57-8.12 (4H, m); 8.34 (2H, d, J=6.4 Hz); 9.16 (IH, br s); 10.80 ppm (IH, br s). HPLC analysis on Alltima C 18 : impurities 4.8% (column size: 4.6x150 mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 30:70; sample concentration 1.0 mg/ml; flow rate 1.15 mL/min; detector UV 254 nm.) Anal. Calcd for C 17
H
1 NsO 5 0 4 S, %: C 52.43, H 4.92, N 17.98. Found, %: C 30 52.37, H 4.89, N 17.69.
WO 03/082288 PCT/GB03/01463 -143 Example 63 (E)-3-(3-{[4-(2,2-Diphenylethyl)-l-piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide (PX118913) 5 The title compound was obtained using methods analogous to those described above. M.p. 117 0 C (decomposes). 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.42-2.62 (4H, m, overlapped with a signal of DMSO); 2.70-2.87 (4H, m); 2.92 (2H, d, J=7.3 Hz); 4.18 (IH t, J= 7.3 Hz); 6.58 (IH, d, J=15.8 Hz); 7.02-7.35 (10OH, m); 7.53 (IH, d, J= 15.8 Hz); 7.61-7.70 (2H, m); 7.80-7.92 (2H, m); 9.14 (IH, br s); 10.80 ppm (IH, br s). HPLC analysis on 10 Omnisphere C18: impurities 4.5% (column size 4.6x150 mm; mobile phase acetonitrile 0.1 M phosphate buffer (pH 2.5), 40:60; sample concentration 0.5 mg/ml; flow rate: 1.2 mL/min; detector UV 220 nm.) Anal. Calcd. for C 27
H
29
N
3 0 4 S * 0.2 M Et 2 0 containing 1.8% of inorganic impurities, %: C 64.75, H 6.06, N 8.15. Found, %: C 64.76, H 6.07, N 8.19. 15 Example 64 (E)-N-Hydroxy-3-[3-({4-[2-(2naphthyl)ethyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenamide (PX118914) The title compound was obtained using methods analogous to those described above. 20 M.p. 1840C. 'H NMR (DMSO-d 6 , HMDSO), 5: 2.38-3.07 (12H, m, partly overlapped with a signal ofDMSO); 6.63 (IH, d, J=16.0 Hz); 7.20-7.54 (4H, m); 7.57-7.98 (8H, m); 9.16 (IH, br s); 10.78 ppm (IH, br s). HPLC analysis on Alltima C18: impurities 1.0% (column size 4.6xl50mm; mobile phase acetonitrile - 0.1 M phosphate buffer (pH 2.5), 35:65; sample concentration 1.0 mg/ml; flow rate 1.2 mL/min; detector UV 220 nm). Anal. Calcd. for 25 C 25
H
27
N
3 0 4 S, %: C 64.50, H 5.85, N 9.03. Found, %: C 64.34, H 5.74, N 9.02. Example 65 3-(4-Chlorosulfonylphenyl)acrylic acid (8) 30 To neat chlorosulfonic acid (26.5 mL, 0.4 mol) at 180C temperature slowly cinnamic acid (1) (7.35 g, 0.05 mol) was added. As the reaction proceeded, hydrogen chloride gas evolved. The reaction mixture was stirred successively at 2000 for 3 hours and at 420C for 3 hours. The dark, viscous syrup was poured into ice water, and the precipitated solid was filtered and washed with water. The title compound was obtained (6.8 g, 55%) as a 35 white solid. 1 H NMR (DMSO-d 6 , HMDSO), 5:6.55 (1H, d, J=16.0 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15 (1H, br s).
WO 03/082288 PCT/GB03/01463 -144 Example 66 (E)-3-[4-({4-[3-(Trifluoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoic acid (9a) 5 To a suspension of 1-(a,a,a-trifluoro-m-tolyl)piperazine hydrochloride (0.43 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO 3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction 10 mixture was poured into water (50 mL) and the pH of the medium was brought to -4 with 2 N HCI. The precipitated solid was filtered, washed with water, and dried in vacuum to give the title compound (0.59 g, 82%). 1 H NMR (DMSO-d 6 , HMDSO), 5: 2.96-3.67 (8H, m, overlapped with a signal of water); 6.74 (1H, d, J=16.3 Hz); 7.01-7.57 (4H, m); 7.67 (1H, d, J=16.3 Hz); 7.82 (2H, d, J=8.4 Hz); 8.00 (2H, d, J=8.4 Hz); 12.71 (1H, br s). 15 Example 67 (E)-3-[4-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyll]-2-propenoic acid (9b) 20 To a suspension of 1-bis(4-fluorophenyl)methyl piperazine (0.47 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO 3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4 chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL), the pH of the medium was brought to -4 with 2 N HCI, and 25 extracted with ethyl acetate. The extract was washed successively with water, brine, and dried (Na 2 SO4). The solvent was removed and the crude product was crystallized from dioxane to give the title compound (0.58 g, 63%) as a white solid. 1 H NMR (DMSO-d 6 , HMDSO), 6: 2.19-2.50 (4H, m, overlapped with a signal of DMSO); 2.80-3.12 (4H, m); 4.42 (1H, s); 6.78 (1H, d, J=16.0 Hz); 7.11 (4H, t, J=9.0 Hz); 7.41 (4H, dd, J=8.6 and 5.6 30 Hz); 7.72 (1H, d, J=16.0 Hz); 7.78 (2H, d, J=8.2 Hz); 8.00 (2H, d, J=8.2 Hz); 12.68 (1H, br s).
WO 03/082288 PCT/GB03/01463 -145 Example 68 (E)-3-[4-({4-[3-(Trifl uoromethyl)phenyl]-1-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (1 Oa) 5 To a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-1l-piperazinyl}sulfonyl)phenyl] 2-propenoic acid (9a) (0.30 g, 0.69 mmol) in dichloromethane (7 mL) oxalyl chloride (0.2 mL, 2.4 mmol) and a drop of dimethylformamide were added. The reaction mixture was stirred at ambient temperature for 0.5 hours and at 42 0 C for 1 hour. The reaction mixture was evaporated and the residue was dried in vacuum to give (E)-3-[4-({4-[3 10 (trifluoromethyl)phenyl]-1l-piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in a form of a crude product. Example 69 (E)-3-[4-({4-[Bis(4-fluorophenyl)methyl]- 1 -piperazinyl}sulfonyl)phenyl]-2-propenoyl 15 chloride (10b) To a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1l-piperazinyl}sulfonyl)phenyl]-2 propenoic acid (9b) (0.25 g,0.5 mmol) in dichloromethane (7 mL) oxalyl chloride (0.15 mL, 1.75 mmol) and a drop of dimethylformamide were added. The reaction mixture was 20 stirred at ambient temperature for 1 hour, then the mixture was evaporated and the residue was dried in vacuum to give (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in a form of a crude product. 25 Example 70 (E)-N-Hydroxy-3-[4-({4-[3-(trifluoromethyl)phenyl]-1 -piperazinyl}-sulfonyl)phenyl]-2 propenamide (PX1 18937) To a suspension of hydroxylamine hydrochloride (0.24 g, 3.4 mmol) in tetrahydrofuran 30 (5.0 mL) a solution of NaHCO 3 (0.40 g, 4.8 mmol) in water (6 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a suspension of (E)-3-[4-({4-[3-(trifluoromethyl)phenyl]-l piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10a) (0.31 g) in tetrahydrofuran (5 mL) and the mixture was stirred at ambient temperature for 0.5 hours. The mixture was 35 poured into water (25 mL), the precipitate was filtered, washed with water, ether, and dried to give the title compound (0.23 g, 73%). M.p. 178-179 0 C. 1 H NMR (DMSO-d 6
,
WO 03/082288 PCT/GB03/01463 - 146 HMDSO), 6: 2.95-3.10 (4H, m); 3.23-3.40 (4H, m, overlapped with a signal of water); 6.62 (1H, d, J=15.9 Hz); 7.09 (1H, d, J=7.7 Hz); 7.16 (1H, s); 7.19 (1H, d, J=8.0 Hz); 7.40 (1H, t, J=7.7 Hz); 7.54 (1H, d, J=15.9 Hz); 7.80 (2H, d, J=8.4 Hz); 7.83 (2H, d, J=8.4 Hz); 9.35 (1H, br s); 10.72 (1 H, br s). HPLC analysis on Omnispher 5 C 18 column: impurities 3.5% 5 (column size 4.6x1 50 mm; mobile phase acetonitrile - 0.1M acetate buffer (pH 5.0), 50:50; sample concentration 1 mg/ml; flow rate 1.3 mL/min; detector UV 254 nm). Anal. Calcd for C 20
H
2 0
F
3
N
3 0 4 S, %: C 52.74, H 4.43, N 9.23, S 7.04. Found, %: C 52.04, H 4.29, N 8.86, S 7.20. 10 Example 71 (E)-3-[4-({4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl}sulfonyl)phenyl]-N-hydroxy-2 propenamide (PX118965) To a suspension of hydroxylamine hydrochloride (0.18 g, 2.5 mmol) in tetrahydrofuran 15 (5.0 mL) a solution of NaHCO 3 (0.30 g, 3.5 mmol) in water (5 mL) was added and the resultant mixture was stirred at ambient temperature for 5 minutes. The reaction mixture was added to a solution of (E)-3-[4-({4-[bis(4-fluorophenyl)methyl]-1 piperazinyl}sulfonyl)phenyl]-2-propenoyl chloride (10b) (0.26 g) in tetrahydrofuran (5 mL) and the obtained mixture was stirred at ambient temperature for 0.5 hours. The mixture 20 was poured into water (25 mL), extracted with ethyl acetate, the extract was washed with water, brine, and dried (Na 2 SO4). The solvent was removed and the residue was chromatographed on silica gel with chloroform - isopropanol (9:1) as eluent to give the title compound (0.087 g, 34%). M.p. 125-126 0 C. 'H NMR (DMSO-de, HMDSO), 6: 2.26 2.42 (4H, m); 2.81-3.00 (4H, m); 4.39 (1H, s); 6.64 (1H, d, J=15.8 Hz); 7.07 (4H, t, J=8.6 25 Hz); 7.37 (4H, dd, J=8.4 and 5.6 Hz); 7.57 (1H, d, J=15.8 Hz); 7.74 (2H, d, J=8.0 Hz); 7.83 (2H, d, J=8.0 Hz); 9.19 (1H, s); 10.93 (1H, s). HPLC analysis on Alltima C 1 8 column: impurities 2% (column size 4.6x1 50 mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), 70:30; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min; detector: UV 215 nm). Anal. Calcd for C 26
H
25
F
2
N
3 0 4 S * 0.3 Et 2 0 * 0.2 iso-PrOH * 0.1 CHCI 3 (an 30 exhaustively dried material contains all the indicated traces of solvents (PMR)), %: C 59.87, H 5.35, N 7.51, S 5.73. Found, %: C 59.85, H 5.36, N 7.29, S 5.60.
WO 03/082288 PCT/GB03/01463 -147 Example 72 1-(1,3-Benzodioxol-5-ylmethyl)-4-({-[(E)-3-(hydroxyamino)-3-oxo-1 propenyl]phenyl}sulfonyl)piperazin-1-ium dihydrogen phosphate (PX118882) 5 The title compound was obtained using methods analogous to those described above. M.p. 210-211 oC. 1 H NMR (DMSO-d 6 , HMDSO) 5: 2.30-2.45 (4H, m, overlapped with a signal of DMSO); 2.82-2.96 (4H, m); 3.36 (2H, s); 3.89-4.67 (br s, interchangeable protons); 5.95 (2H, s); 6.62 (IH, d, J=15.8 Hz); 6.68 (IH, d, J=7.8 Hz); 6.77 (IH, s); 6.79 (IH, d, J=7.8 Hz); 7.53 (2H, d, J=15.8 Hz); 7.73 (2H, d, J=8.0 Hz), 7.81 (2H, d, J=8.0 Hz). 10 HPLC analysis on Omnispher 5 C18: impurities 2.5% (column size 4.6x150mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), 20:80; sample concentration 0.5 mg/ml; flow rate 1.5 ml/min; detector UV 220 nm). Anal. Calcd. for C 21
H
23
N
3 0 6 S * H 3
PO
4 * 0.25 NaH 2
PO
4 , %: C 43.98, H 4.66, N 7.33, S 5.59. Found, %: C 43.59, H 4.75, N 7.50, S 5.70. 15 Example 73 (E)-N-Hydroxy-3-(4-{[4-(4-nitorphenyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenamide (PX118918) 20 The title compound was obtained using methods analogous to those described above. M. p. 199-2000C. 1 H NMR (DMSO-dB, HMDSO) 6: 2.97-3.09 (4H, m); 3.49-3.62 (4H, m); 6.61 (1H, d, J=15.7 Hz); 6.99 (2H, d, J=9.2 Hz); 7.52 (1H, d, J=15.7 Hz); 7.78 (2H, d, J=9.0 Hz); 7.81 (2H, d, J=9.0 Hz); 8.02 (2H, d, J=9.2 Hz); 9.17 (1H, s); 10.91 (1H, s). HPLC analysis on Omnispher 5 C 18 : impurities 3.0% (column size 4.6x150mm; mobile phase 25 acetonitrile - 0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.25 mg/ml; flow rate 1.5 mL/min; detector UV 270 nm). Anal. Calcd. for C 1 9
H
20
N
4 0 6 S, %: C 52.77, H 4.66, N 12.96, S 7.41. Found, %: C 52.56, H 4.74, N 12.41, S 7.28. Example 74 30 (E)-3-(4-{[4-(2-Fluorophenyl)-I -piperazinyl]sulfonyl}phenyl)-N-hydroxy-2-propenamide (PX118891) The title compound was obtained using methods analogous to those described above. M. p. 196-197°C. 1H NMR (DMSO-d 6 , HMDSO) 5: 3.00-3.14 (8H, m); 6.63 (IH, d, J=15.8 Hz); 35 6.92- 7.18 (4H, m); 7.55 (IH, d, J=15.8 Hz); 7.80 (2H, d, J=8.6 Hz); 7.84 (2H, d, J=8.6 Hz); 9.16 (IH, s); 10.92 (IH, s). HPLC analysis on AIItima C18: impurities 3.5% (column size WO 03/082288 PCT/GB03/01463 -148 4.6x150mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), 50:50; sample concentration 1.0 mg/ml; flow rate 1.0 mLlmin; detector UV 254 nm.) Anal. Calcd. for Cj 9
H
20
FN
3 0 4 S * 0.2 EtOAc, %: C 56.21, H 5.15, N 9.93, S 7.58. Found, %: C 56.07, H 5.10, N 9.97, S 7.60. 5 Example 75 (E)-N-Hydroxy-3-(4-{[4-(3-methoxyphenyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenamide (PX118892) 10 The title compound was obtained using methods analogous to those described above. M. p. 199-2000C. 'H NMR (DMSO-d 6 , HMDSO) 6: 2.95-3.06 (4H, m); 3.13-3.25 (4H, m); 3.68 (3H, s); 6.38 (IH, d, J=8.0 Hz); 6.42 (IH, s); 6.47 (IH, d, J=8.2 Hz); 6.61 (IH, d, J=16.0 Hz); 7.09 (IH, t, J=8.0 Hz); 7.54 (IH, d, J=16.0 Hz); 7.78 (2H, d, J=8.4 Hz); 7.83 (2H, d, J=8.4 Hz); 9.17 (IH, s); 10.91 (IH, br s). HPLC analysis on Omnispher 5 C18: impurities 4.5% 15 (column size 4.6x150mm; mobile phase acetonitrile - 0. 1M phosphate buffer (pH 2.5), 45:55; sample concentration 0.15 mg/ml; flow rate 1.2 mL/min; detector UV 254 nm). Anal. Calcd. for C 20
H
23
N
3 0 5 S * 0.1 EtOAc * 0.2 H 2 0, %: C 57.00, H 5.67, N 9.77, S 7.46. Found, %: C 57.04, H 5.52, N 9.64, S 7.38. 20 Example 76 (E)-N-Hydroxy-3-(4-{[4-(2-methoxyphenyl)-1 -piperazinyl]sulfonyl}phenyl)-2-propenamide (PX118905) The title compound was obtained using methods analogous to those described above. M. 25 p. 225-2260C. ,H NMR (DMSO-d 6 , HMDSO) 6: 2.89-3.13 (8H, m); 3.70 (3H, s); 6.63 (IH, d, J=15.8 Hz); 6.83-7.00 (4H, m); 7.56 (IH, d, J=15.8 Hz); 7.80 (2H, d, J=8.2 Hz); 7.85 (2H, d, J=8.2 Hz); 9.18 (IH, br s); 10.93 (IH, br s). HPLC analysis on Omnispher 5 C18: impurities 4.5%. (column size 4.6x150mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), 40:60; sample concentration 0.2 mg/ml; flow rate 1.2 mL/min; detector UV 30 254 nm). Anal. Calcd. for C 2 0
H
2 3
N
3 0 5 S * 0.2 EtOAc * 0.2 H 2 0, %: C 56.95, H 5.74, N 9.58, S 7.31. Found, %: C 56.95, H 5.66, N 9.40, S 7.54.
WO 03/082288 PCT/GB03/01463 -149 Example 77 3-{4-[4-(3-Chloro-phenyl)-piperazine-1 -sulfonyl]-phenyl}-N-hydroxy-acrylamide (PX118906) 5 The title compound was obtained using methods analogous to those described above. Example 78 N-Hydroxy-3-[4-(4-pyrimidin-2-yl-piperazine-1l-sulfonyl)-phenyl]-acrylamide (PX1 18907) 10 The title compound was obtained using methods analogous to those described above. Example 79 3-[4-(4-Benzhydryl-piperazine-1l-sulfonyl)-phenyl-N-hydroxy-acrylamide (PX118910) 15 The title compound was obtained using methods analogous to those described above. Example 80 N-Hydroxy-3-[4-(3-methyl-4-m-tolyl-piperazine-1 -sulfonyl)-phenyl]-acrylamide (PX118911) 20 The title compound was obtained using methods analogous to those described above. Method E - General Synthesis of 1-Acylpiperazines Appropriate carboxylic acid (1-2 mmol) and hydroxybenztriazole (1 eq) were suspended in 25 chloroform (2 mL/1 mmol) and a solution of 1,3-dicylcohexylcarbodiimide (DCC) (1 eq) in a minimal amount of dimethylformamide was added. The mixture was stirred for 30 minutes at room temperature to give white suspension. The mixture was transferred slowly to a pre-cooled solution of anhydrous piperazine (5 eq) in chloroform (1 mL/1 mmol). The reaction was stirred for 4 hours at room temperature, the white suspension 30 (DCU) was filtered, and the filtrate was extracted with 2 M HCl. The HCI extracts were basified with 2 M NaOH to pH 9, extracted with ethyl acetate, and the organic extract was washed with brine, dried (Na 2
SO
4 ), and evaporated under reduced pressure. The crude product was used without further purification, or was purified on silica gel (20 g) with methanol-NH 4 OH (ca. 95:5 to 90:10) as eluent. 35 WO 03/082288 PCT/GB03/01463 - 150 Example 81 2-Naphthyl(1-piperazinyl)methanone (13a) The title compound was prepared from naphthalene 2-carboxylic acid (12a), using Method 5 E, yield 94%. 1 H NMR (CDCI 3 , HMDS), 6: 1.92(s, 1H); 2.87(t, J=5.0 Hz, 4H); 3.63(t, J=5.0 Hz, 4H); 7.43-7.74(m, 3H); 7.89-8.12(m, 4H). Example 82 2-(5-Methoxy-1H-indol-3-yl)-1-(1-piperazinyl)-1-ethanone (13b) 10 The title compound was prepared from 2-(5-methoxy-1 H-indol-3-yl)acetic acid (12bI), using Method E, yield 75%. 1 H NMR (CDCI 3 , HMDS), 6: 1.61(s, 1H); 2.63(t, J=5.0 Hz, 2H); 2.78(t, J=5.0 Hz, 2H); 3.45(t, J=5.0 Hz, 2H); 3.65(t, J=5.0 Hz, 2H); 3.78(s, 2H); 3.83(s, 3H); 6.78(dd, J=8.8 and 3.0 Hz, 1H); 7.06(t, J= 3.0 Hz, 2H); 7.22(d, J=8.8 Hz, 1H); 15 8.27(s, 1H). Example 83 2-(2-Naphthyloxy)-1-(1-piperazinyl)-1l-ethanone (13c) 20 The title compound was prepared from 2-(2-naphthyloxy)acetic acid (2c), using Method E, yield 97%. 1 H NMR (CDCl 3 , HMDS), 6: 1.69(s, 1H); 2.83(t, J=5.0 Hz, 4H); 3.61(t, J=5.0 Hz, 4H); 4.81(s, 2H); 7.12-7.58(m, 4H); 7.69-7.92(m, 3H). Example 84 25 2-(1-Naphthyloxy)-1l-(1-piperazinyl)-1l-ethanone (13d) The title compound was prepared from 2-(1-naphthyloxy)acetic acid (2d), using Method E, yield 82%. 1 H NMR (CDCI 3 , HMDS), 6: 1.87(s, 1H); 2.63(t, J=5.0 Hz, 2H); 2.83(t, J=5.0 Hz, 2H); 3.45(t, J=5.0 Hz, 2H); 3.65(t, J=5.0 Hz, 2H); 3.89(s, 2H); 7.29-7.61(m, 3H); 7.65 30 7.96(m, 4H). Example 85 2-(1-Benzothiophen-3-yl)-1l-(1-piperazinyl)-1l-ethanone (13e) 35 The title compound was prepared from 2-(1-benzothiophen-3-yl)acetic acid (12e), using Method E, yield 92%. 'H NMR (CDC 3 , HMDS), 6: 1.61(s, 1H); 2.67(t, J=5.0 Hz, 2H); WO 03/082288 PCT/GB03/01463 - 151 2.83(t, J=5.0 Hz, 2H); 3.43(t, J=5.0 Hz, 2H); 3.67(t, J=5.0 Hz, 2H); 3.81(s, 2H); 7.21 7.54(m, 3H); 7.69-7.98(m, 2H). Example 86 5 3-(1H-Indol-3-yl)-1-(1-piperazinyl)-1-propanone (13f) The title compound was prepared from 3-(1H-indol-3-yl)propanoic acid (12f), using Method E, yield 79%. 1 H NMR (CDCl 3 , HMDS), 6: 2.03(s, 1H); 2.54-2.89(m, 6H); 3.03 3.21(m, 2H); 3.34(t, J=5.0 Hz, 2H); 3.58(t, J=5.0 Hz, 2H); 7.00-7.45(m, 4H); 7.52-7.74(m, 10 1H); 8.13(bs, 1H). Example 87 1 H-Indol-3-yl(1-piperazinyl)methanone (13c) 15 The title compound was prepared from 1H-indole-3-carboxylic acid (I2g), using Method E, yield 39%. 1H NMR (CDCI 3 , HMDS), 6: 1.67(s, 1H); 2.89(t, J=5.0 Hz, 4H); 3.69(t, J=5.0 Hz, 4H); 7.09-7.43(m, 4H); 7.63-7.87(m, 1 H); 9.27(bs, 1H). Example 88 20 Tert-butyl 4-benzoyl-1l-piperazinecarboxylate (15h) To a solution of N-Boc-piperazine (14) (1.00 g, 5.37 mmol) in dioxane (5 mL), a solution of NaOH (0.50 g, 12.9 mmol) in water (5 mL) followed by a solution of benzoyl chloride (0.75 mL, 6.44 mmol) in dioxane (2 mL) under vigorous stirring were added. The reaction 25 mixture was stirred at ambient temperature for 4 hours, diluted with brine (20 mL), and extracted with ethyl acetate (2 x 25 mL). The organic extract was washed successively with brine (20 mL), saturated NaHCO 3 (20 mL), saturated KH 2
PO
4 (20 mL), and dried (Na 2
SO
4 ). The solvents were evaporated to give the title compound (1.400 g, 90%) which was used in the next step of the synthesis without further purification. 1 H NMR (CDCl 3 , 30 HMDS), 6: 1.41(s, 9H), 2.86(t, J=5.0 Hz, 4H); 3.62(t, J=5.0 Hz, 4H); 7.34(s, 5H). Method F - General Synthesis of Tert-Butyl 1-Piperazinecarboxylates A solution of appropriate acid 12i-k (2.75 mmol) in anhydrous dimethylformamide (4.5 35 mL) was cooled in ice bath under argon and carbonyldiimidazole (0.490 g, 3.01 mmol) was added. The mixture was stirred for 30 minutes, then a solution of N-Boc-piperazine WO 03/082288 PCT/GB03/01463 - 152 14 (2.75 mmol) in dimethylformamide (3 mL) was added. The mixture was stirred at ice bath temperature for 1 hour, followed by 20 hours at room temperature, diluted with brine (20 mL), and extracted with ethyl acetate (3 x 25 mL). The organic phase was washed successively with brine (20 mL), saturated KH 2
PO
4 (20 mL), brine (20 mL), and dried 5 (Na 2 SO4). The solvent was evaporated and the crude product was used in a further step of the synthesis without additional purification, or was purified on silica gel (20 g) with ethyl acetate as eluent. Example 89 10 tert-Butyl 4-[4-(dimethylamino)benzoyl]-1l-piperazinecarboxylate (15i) The title compound was prepared from 4-(dimethylamino)benzoic acid (12i), using Method F, yield 61%. 1 H NMR (CDCI 3 , HMDS), 5: 1.45(s, 9H); 2.98(s, 6H); 3.29-3.74(m, 8H); 6.69(d, J=8.8 Hz, 2H); 7.36(d, J=8.8 Hz, 2H). 15 Example 90 tert-Butyl 4-(4-cyanobenzoyl)-1l-piperazinecarboxylate (15) The title compound was prepared from 4-cyanobenzoic acid (12J), using Method F, yield 20 96%. 1 H NMR (CDC 3 , HMDS), 6: 1.40(s, 9H); 2.87(t, J=5.0 Hz, 4H); 3.63(t, J=5.0 Hz, 4H); 6.70(d, J=8.8 Hz, 2H); 7.12(d, J=8.8 Hz, 2H). Example 91 tert-Butyl 4-{2-[4-(dimethylamino)phenyl]acetyl}-1l-piperazinecarboxylate (15k) 25 The title compound was prepared from 2-[4-(dimethylamino)phenyl]acetic acid (12k), using Method F, yield 60%. 1 H NMR (CDCI 3 , HMDS), 6: 1.43(s, 9H); 2.92(s, 6H); 3.07 3.78(m, 8H); 3.65(s, 2H); 6.72(d, J=8.8 Hz, 2H); 7.14(d, J=8.8 Hz, 2H). 30 Method G - General Synthesis of 1-Acylpiperazines A solution of an appropriate N-Boc-piperazine derivative 15h-k (2.5 mmol) in 1 N HCI methanol (12.5 mL) (made in situ from AcCI and MeOH) was stirred for 2 hours at ambient temperature, and then the mixture was evaporated. To the residue, water (30 35 mL) was added, the mixture was washed with diethyl ether, and the pH of the aqueous phase was brought to 9 with 2 M NaOH. The reaction product was extracted with WO 03/082288 PCT/GB03/01463 -153 chloroform (3 x 25 mL), the organic extract was washed with brine (25 mL), and dried (Na 2
SO
4 ). The solvent was evaporated and the crude product was used in a further step of the synthesis without additional purification, or was purified on silica gel (20 g) with methanol-NH 4 OH (9:1) as eluent. 5 Example 92 Phenyl(1-piperazinyl)methanone (13h) The title compound was prepared from tert-butyl 4-benzoyl-1-piperazinecarboxylate (15h), 10 using Method G, yield 87%. 1 H NMR (CDCI3, HMDS), 6:1.81(s, 1H); 2.76(t, J=5.0 Hz, 4H); 3.56(bs, 4H); 7.41(s, 5H). Example 93 [4-(Dimethylamino)phenyl](1-piperazinyl)methanone (13i) 15 The title compound was prepared from tert-butyl 4-[4-(dimethylamino)benzoyl]-l piperazinecarboxylate (15i), using Method G, yield 82%. 1 H NMR (CDC3, HMDS), 5: 1.91 (s, 1H); 2.87(t, J=5.0 Hz, 4H); 2.98(s, 6H); 3.63(t, J=5.0 Hz, 4H); 6.67(d, J=8.8 Hz, 2H); 7.34(d, J=8.8 Hz, 2H). 20 Example 94 4-(1-Piperazinylcarbonyl)benzonitrile (13j) The title compound was prepared from tert-butyl 4-(4-cyanobenzoyl)-1 25 piperazinecarboxylate (15), using Method G, yield 62%. 1 H NMR (CDC3, HMDS), 6: 1.92(s, 1H); 2.69-3.02(m, 4H); 3.14-3.92(m, 4H); 7.49(d, J=8.8 Hz, 2H); 7.72(d, J=8.8 Hz, 2H). Example 95 30 8-(4-{2-[4-(Dimethylamino)phenyl]acetyl}-1-piperazinyl)-N-hydroxy-8-oxooctanamide (13k) The title compound was prepared from tert-butyl 4-(2-[4-(dimethylamino)phenyl]acetyl}-1 piperazinecarboxylate (15k), using Method G, yield 80%. 'H NMR (CDC3, HMDS), 6: 1.63(s, 1H); 2.63(t, J=5.0 Hz, 2H); 2.78(t, J=5.0 Hz, 2H); 2.92(s, 6H); 3.41(t, J=5.0 Hz, 35 2H); 3.58(t, J=5.0 Hz, 2H); 3.65(s, 2H); 6.99(d, J=8.8 Hz, 2H); 7.1 1(d, J=8.8 Hz, 2H).
WO 03/082288 PCT/GB03/01463 -154 Method H - General Synthesis of N-Monosubstituted Piperazines To a suspension of LiAIH 4 (2.5 eq) in anhydrous tetrahydrofuran (2-3 mL/1 mmol) under argon atmosphere, a solution of appropriate N-acylpiperazine 13b,c,f.gq,k (1 eq) in 5 tetrahydrofuran (1.5 mLl mmol) was added, and the mixture was stirred at reflux temperature until the initial compound disappeared (3-7 hours on average). The reaction mixture was allowed to cool to room temperature and methanol, water, and 1N NaOH were carefully added. The reaction mixture was stirred for 2 hours at room temperature and the mixture passed through a celite pad. The filtrate was evaporated and the residue 10 was purified on silica gel (20 g) with methanol-NH 4 OH (9:1) as eluent to give the expected piperazine product. Example 96 5-Methoxy-3-[2-(1-piperazinyl)ethyl]-1 H-indole (16b) 15 The title compound was prepared from 2-(5-methoxy-1H-indol-3-yl)-1-(1-piperazinyl)-1 ethanone (13b), using Method H, yield 38%. 1 H NMR (CDCI 3 , HMDS), 6: 1.61(s, 1H); 2.47-2.81(m, 6H); 2.87-3.09(m, 6H); 3.85(s, 3H); 6.85(dd, J=8.8 and 3.0 Hz, 1H); 7.05(t, J= 3.0 Hz, 2H); 7.25(d, J=8.8 Hz, 1H); 7.83(s, 1H). 20 Example 97 1-[2-(2-Naphthyloxy)ethyl]piperazine (16c) The title compound was prepared from 2-(2-naphthyloxy)-1l-(1-piperazinyl)-l-ethanone 25 (13c), using Method H, yield 43%. 1 H NMR (CDCI 3 , HMDS), 6: 1.48(s, 1H); 2.56(t, J=5.0 Hz, 4H); 2.85(t, J=6.0 Hz, 2H); 2.92(t, J=5.0 Hz, 4H); 4.25(t, J=6.0 Hz, 2H); 7.05-7.58(m, 4H); 7.65-7.89(m, 3H). Example 98 30 3-[3-(1 -Piperazinyl)propyl]-I H-indole (16f) The title compound was prepared from 3-(1H-indol-3-yl)-1-(1-piperazinyl)-1 -propanone (13f), using Method H, yield 74%. 'H NMR (DMSO, HMDS), 6: 1.69(t, J=7.0 Hz, 1H); 1.78(t, J=7.0 Hz, 1 H); 2.12-2.34(m, 6H); 2.36-2.47(1H, overlapped with DMSO signal); 35 2.49-2.76(m, 6H); 6.67-7.00(m, 3H); 7.05-7.45(m, 2H); 10.49(s, 1H).
WO 03/082288 PCT/GB03/01463 -155 Example 99 3-(1 -Piperazinylmethyl)-1 H-indole (16g) The title compound was prepared from 1 H-indol-3-yl(1-piperazinyl)methanone (1ag), 5 using Method H, yield 63%. 'H NMR (CDC3, HMDS), 6: 1.81(s, 1H); 2.49(t, J=5.0 Hz, 4H); 2.89(t, J=5.0 Hz, 4H); 3.72(s, 2H); 7.05-7.52(m, 4H); 7.65-7.83(m, 1H); 8.14(bs, 1H). Example 100 N,N-Dimethyl-4-[2-(1-piperazinyl)ethyl]aniline (16k) 10 The title compound was prepared from 8-(4-{2-[4-(dimethylamino)phenyl] acetyl}-l piperazinyl)-N-hydroxy-8-oxooctanamide (13k), using Method H, yield 82%. 1 H NMR (CDCI3, HMDS), 6: 1.74(s, 1H); 2.34-2.72(m, 8H); 2.89(s, 6H); 2.81-3.03(m, 4H); 6.72(d, J=8.8 Hz, 2H); 7.09(d, J=8.8 Hz, 2H). 15 Method J - General Synthesis of Amidoesters A solution of dicarbonic acid monoethyl (or monomethyl) ester 18a or 18b (2.73 mmol) in anhydrous tetrahydrofuran (5 mL) under argon atmosphere was cooled in an ice bath and 20 to the solution carbonyldiimidazole (0.500 g, 3.08 mmol) was added. The mixture was stirred for 1 hour at ice bath temperature, then appropriate piperazine (2.73 mmol) was added. The reaction mixture was stirred at room temperature for 20 hours, concentrated under vacuum, and partitioned between brine (30 mL) and ethyl acetate (40 mL). The organic layer was washed successively with water (25 mL), 5% citric acid (25 mL), brine 25 (25 mL), and dried (MgSO 4 ). The solvent was evaporated and the residue was chromatographed on silica gel (20 g) with petroleum ether-ethyl acetate as eluent affording the corresponding reaction product. Example 101 30 8-Oxo-8-(4-phenyl-piperazin-1 -yl)-octanoic acid methyl ester (19a) The title compound was obtained from suberic acid monomethyl ester (18b) and N phenylpiperazine (17a) (commercially available) using Method J, yield 88%. 'H NMR (DMSO-d 6 , HMDSO), 6: 1.05-1.72 (m, 8H); 2.02-2.30 (m, 8H); 3.30-3.60 (m, 4H); 3.51 (s, 35 3H); 7.21-7.51 (m, 5H).
WO 03/082288 PCT/GB03/01463 - 156 Example 102 Ethyl 7-(4-benzhydryl-1l-piperazinyl)-7-oxoheptanoate (19b) The title compound was obtained from pimelic acid monoethyl ester (18a) and 1 5 (diphenylmethyl)piperazine (17b) (commercially available) using Method J, yield 80%. 1 H NMR (DMSO-de, HMDSO), 5:1.04-1.62 (m, 9H); 2.12-2.36 (m, 8H); 3.35-3.50 (m, 4H); 4.17 (q, 2H, J=7.3 Hz); 4.31 (s, 1H); 7.02-7.59 (m, 10H). Example 103 10 Ethyl 7-oxo-7-(4-phenyl-1 -piperazinyl)heptanoate (19c) The title compound was obtained from pimelic acid monoethyl ester (18a) and N phenylpiperazine (17a) (commercially available) using Method J, yield 88%. 'H NMR (DMSO-de, HMDSO), 6:1.12-1.62 (m, 9H); 1.97-2.35 (m, 8H); 3.27-3.59 (m, 4H); 4.17 (q, 15 2H, J=7.2 Hz); 7.03-7.51 (m, 5H). Example 104 Methyl 8-(4-benzhydryl-1l-piperazinyl)-8-oxooctanoate (19d) 20 The title compound was obtained from suberic acid monomethyl ester (18b) and 1 (diphenylmethyl)piperazine (17b) (commercially available) using Method J, yield 91%. 1 H NMR (DMSO-d 6 , HMDSO), 5:1.02-1.67 (m, 8H); 2.09-2.38 (m, 8H); 3.33-3.51 (m, 4H); 3.56 (s, 3H); 4.29 (s, 1H); 7.09-7.56 (m, 10H). 25 Example 105 Methyl 8-[4-(2-methoxyphenyl)-1l-piperazinyl]-8-oxooctanoate (19e) The title compound was obtained from suberic acid monomethyl ester (18b) and 1-(2 methoxyphenyl)piperazine hydrochloride (17c) (commercially available) (before the 30 addition of hydrochloride (17c), triethylamine (3.0 mmol) was added to the reaction mixture), using Method J, yield 87%. 1 H NMR (DMSO-de, HMDSO), 6:1.12-1.60 (m, 8H); 1.97-2.82 (m, 8H, overlapped with a signal of DMSO); 3.40-3.62 (m, 7H); 3.75 (s, 3H); 6.92-7.15 (m, 4H).
WO 03/082288 PCT/GB03/01463 -157 Method K - General Synthesis of Amidoesters To a solution of dicarbonic acid monoethyl (or monomethyl) ester 18a or 18b (2.75 mmol) in anhydrous dichloromethane (10 mL) oxalyl chloride (0.84 mL, 9.63 mmol) and a drop of 5 dimethylformamide were added, and the resulting mixture was stirred for 30 minutes at room temperature followed by 1 hour at 400C. The solution was carefully evaporated under reduced pressure and the residue was dried in vacuum at 400C. The resulting chloride was dissolved in anhydrous tetrahydrofuran (3 mL) and the obtained solution to a cold suspension (ice bath) of piperazine (2.75 mmol), tetrahydrofuran (10 mL), and 10 saturated NaHCO 3 (10 mL) under vigorous stirring was added. The stirring was continued for 1 hour at ice bath temperature and 20 hours at room temperature. The mixture was diluted with brine (30 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was washed with brine and dried (Na 2
SO
4 ). The solvent was evaporated and the residue was chromatographed on silica gel (20 g) with benzene - ethyl acetate as eluent to give 15 the corresponding reaction product. Example 106 Ethyl 8-[4-(2-chlorophenyl)-1l-piperazinyl]-8-oxooctanoate (19f) 20 The title compound was obtained from suberic acid monoethyl ester (18c) and 1-(2 chlorophenyl)piperazine (17d) (commercially available) using Method K, yield 80%. 1 H NMR (CDC3, HMDSO), 6: 1.13(t, J=7.0 Hz, 3H); 1.18-1.91(m, 8H); 2.29(t, J=6.0 Hz, 2H); 2.38(t, J=6.0 Hz, 2H); 3.02(t, J=5.0 Hz, 4H); 3.50-3.90(m, 4H); 4.11(q, J=7.0 Hz, 2H); 6.85-7.09(m, 2H); 7.14-7.48(m, 2H). 25 Example 107 Ethyl 8-[4-(3-chlorophenyl)-1l-piperazinyl]-8-oxooctanoate (19cg) The title compound was obtained from suberic acid monoethyl ester (18c) and 1-(3 30 chlorophenyl)piperazine (17e) (commercially available) using Method K, yield 88%. 1 H NMR (CDCi 3 , HMDSO), 5: 1.23(t, J=7.0 Hz, 3H); 1.18-1.79(m, 8H); 2.29(t, J=6.0 Hz, 2H); 2.36(t, J=6.0 Hz, 2H); 3.14(t, J=5.0 Hz, 4H); 3.44-3.87(m, 4H); 4.11(q, J=7.0 Hz, 2H); 6.66-6.92(m, 2H); 7.05-7.37(m, 2H).
WO 03/082288 PCT/GB03/01463 - 158 Example 108 Ethyl 7-[4-(2-chlorophenyl)-1l-piperazinyl]-7-oxoheptanoate (19h) The title compound was obtained from pimelic acid monoethyl ester (18a) and 1-(2 5 chlorophenyl)piperazine (17d) (commercially available) using Method K, yield 79%. 'H NMR (CDCI 3 , HMDSO), 6: 1.23(t, J=7.0 Hz, 3H); 1.18-1.89(m, 6H); 2.29(t, J=6.0 Hz, 2H); 2.38(t, J=6.0 Hz, 2H); 3.00(t, J=5.0 Hz, 4H); 3.49-3.89(m, 4H); 4.12(q, J=7.0 Hz, 2H); 6.85-7.09(m, 2H); 7.14-7.48(m, 2H). 10 Example 109 Ethyl 7-[4-(3-chlorophenyl)-1l-piperazinyl]-7-oxoheptanoate (19i) The title compound was obtained from pimelic acid monoethyl ester (18a) and 1-(3 chlorophenyl)piperazine (17e) (commercially available) using Method K, yield 78%. 'H 15 NMR (CDCl 3 , HMDSO), 5: 1.23(t, J=7.0 Hz, 3H); 1.18-1.89(m, 6H); 2.29(t, J=6.0 Hz, 2H); 2.36(t, J=6.0 Hz, 2H); 3.14(t, J=5.0 Hz, 4H); 3.45-3.89(m, 4H); 4.12(q, J=7.0 Hz, 2H); 6.67-6.94(m, 2H); 7.05-7.38(m, 2H). Method L - General Synthesis of Amidoesters 20 A solution of dicarbonic acid monomethyl (or monoethyl) ester 18a-c (2.75 mmol) in anhydrous dimethylformamide (3 mL) was cooled in ice bath under argon atmosphere and carbonyldiimidazole (490 mg, 3.01 mmol) was added. The mixture was stirred at ice bath temperature for 30 minutes and a solution of appropriate piperazine (2.75 mmol) in 25 dimethylformamide (3 mL) was added (if the piperazine was used in a hydrochloride form triethylamine (1.0 mL) before the piperazine hydrochloride to the reaction mixture was added). The mixture was stirred at ice bath temperature for 1 hour followed by 20 hours at room temperature. Then the reaction mixture was diluted with brine (50 mL) and extracted with ethyl acetate (3 x 25 mL). The organic phase was washed with brine, dried 30 (Na 2 SO4), and the solvent was evaporated. The residue was chromatographed on silica gel with appropriate eluent to give the corresponding reaction product.
WO 03/082288 PCT/GB03/01463 -159 Example 110 Ethyl 8-[4-(2-naphthoyl)-1l-piperazinyl]-8-oxooctanoate (191) The title compound was obtained from suberic acid monoethyl ester (18c) and 2 5 naphthyl(1-piperazinyl)methanone (13a) using Method L, yield 79%. 1 H NMR (CDCI 3 , HMDSO), 6: 1.16(t, J=7.0 Hz, 3H); 1.18-1.65(m, 8H); 2.25(t, J=6.0 Hz, 2H); 2.38(t, J=6.0 Hz, 2H); 3.36-3.65(m, 8H); 4.02(q, J=7.0 Hz, 2H); 7.43-7.74(m, 3H); 7.89-8.12(m, 4H). Example 111 10 Ethyl 8-(4-benzoyl-1 -piperazinyl)-8-oxooctanoate (19k) The title compound was obtained from suberic acid monoethyl ester (18c) and phenyl(1 piperazinyl)methanone (13h) using Method L, yield 89%. 1 H NMR (CDCI 3 , HMDSO), 6: 1.28(t, J=7.0 Hz, 3H); 1.14-1.83(m, 8H); 2.16(t, J=7.0 Hz, 2H); 2.23(t, J=7.0 Hz, 2H); 3.00 15 3.25(m, 4H); 3.49-3.83(m, 4H); 3.98(q, J=7.0 Hz, 2H); 7.39(s, 5H). Example 112 Ethyl 8-{4-[4-(dimethylamino)benzoyl]-1l-piperazinyl}-8-oxooctanoate (191) 20 The title compound was obtained from suberic acid monoethyl ester (18c) and [4 (dimethylamino)phenyl](1-piperazinyl)methanone (13i) using Method L, yield 81%. 1 H NMR (CDCI 3 , HMDSO), 5: 1.27(t, J=7.0 Hz, 3H); 1.15-1.88(m, 8H); 2.34(t, J=7.0 Hz, 2H); 2.52(t, J=6.0 Hz, 2H); 2.88(s, 6H); 3.00-3.21(m, 4H); 3.49-3.87(m, 4H); 4.11(q, J=7.0 Hz, 2H); 7.08(d, J=8.8 Hz, 2H); 7.35(s, 5H). 25 Example 113 Ethyl 8-[4-(4-methoxyphenyl)-1l-piperazinyl]-8-oxooctanoate (19m) The title compound was obtained from suberic acid monoethyl ester (18c) and 1-(4 30 methoxyphenyl)piperazine (17f) (commercially available) using Method L, yield 76%. IH NMR (CDCI 3 , HMDSO), 6: 1.16(t, J=7.0 Hz, 3H); 1.05-1.76(m, 8H); 2.22(t, J=7.0 Hz, 2H); 2.29(t, J=7.0 Hz, 2H); 2.85-3.07(m, 4H); 3.43-3.78(m, 4H); 3.72(s, 3H); 4.05(q, J=7.0 Hz, 2H); 6.83(s, 4H).
WO 03/082288 PCT/GB03/01463 -160 Example 114 Ethyl 8-[4-(3-methoxyphenyl)-1l-piperazinyl]-8-oxooctanoate (19n) The title compound was obtained from suberic acid monoethyl ester (18c) and 1-(3 5 methoxyphenyl)piperazine (17g) (commercially available) using Method L, yield 62%. 1 H NMR (CDCl 3 , HMDSO), 6: 1.29(t, J=7.0 Hz, 3H); 1.16-1.85(m, 8H); 2.16(t, J=7.0 Hz, 2H); 2.22(t, J=7.0 Hz, 2H); 3.00-3.25(m, 4H); 3.49-3.83(m, 4H); 3.65(s, 3H); 3.98(q, J=7.0 Hz, 2H); 6.36-6.67(m, 3H); 7.05-7.23(m, 1 H). 10 Example 115 Ethyl 8-[4-(4-nitrophenyl)-1l-piperazinyl]-8-oxooctanoate (19o) The title compound was obtained from suberic acid monoethyl ester (18c) and 1-(4 nitrophenyl)piperazine (17h) (commercially available) using Method L, yield 67%. 1 H NMR 15 (CDCI 3 , HMDSO),5: 1.23(t, J=7.0 Hz, 3H); 1.07-1.89(m, 8H); 2.29(t, J=7.0 Hz, 2H); 2.36(t, J=7.0 Hz, 2H); 3.25-3.92(m, 8H); 4.12(q, J=7.0 Hz, 2H); 6.83(d, J=8.8 Hz, 2H); 8.14(d, J=8.8 Hz, 2H). Example 116 20 Methyl 8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1-piperazinyl}-8-oxooctanoate (19p) The title compound was obtained from suberic acid monomethyl ester (18b) and 2-(5 methoxy-IH-indol-3-yl)-1-(1-piperazinyl)-1-ethanone (13b) using Method L, yield 76%. IH NMR (CDCl 3 , HMDSO), 5: 1.12-1.89(m, 8H); 2.29(t, J=7.0 Hz, 4H); 3.09-3.74(m, 8H); 25 3.65(s, 3H); 3.83(s, 2H); 3.85(s, 3H); 6.89(dd, J=8.8 and 3.0 Hz, 1H); 7.07(t, J=3.0 Hz, 2H); 7.16-7.35(m, 1H); 8.31(bs, 1H). Example 117 Methyl 8-{4-[2-(2-naphthyloxy)ethyl]-1l-piperazinyl}-8-oxooctanoate (19r) 30 The title compound was obtained from suberic acid monomethyl ester (18b) and 1-[2-(2 naphthyloxy)ethyl]piperazine (16c) using Method L, yield 56%. 1 H NMR (CDCI 3 , HMDSO), 5: 1.14-1.81(m, 8H); 2.29(t, J=7.0 Hz, 4H); 2.43-2.69(m, 4H); 2.87(t, J=5.0 Hz, 2H); 3.32 3.74(m, 4H); 3.63(s, 3H); 4.23(t, J=5.0 Hz, 2H); 7.03-7.23(m, 2H); 7.29-7.52(m, 2H); 7.61 35 7.83(m, 2H).
WO 03/082288 PCT/GB03/01463 -161 Example 118 Ethyl 8-{4-[2-(1-naphthyloxy)acetyl]-1l-piperazinyl}-8-oxooctanoate (19s) The title compound was obtained from suberic acid monoethyl ester (18c) and 2-(1 5 naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13d) using Method L, yield 65%. 1 H NMR
(CDCI
3 , HMDSO), 6: 1.23(t, J=7.0 Hz, 3H); 1.18-1.85(m, 8H); 2.27(t, J=7.0 Hz, 4H); 3.10 3.81(m, 8H); 3.92(s, 2H); 4.12(q, J=7.0 Hz, 2H); 7.32-7.59(m, 3H); 7.65-7.94(m, 4H). Example 119 10 Methyl 8-{4-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1l-piperazinyl}-8-oxooctanoate (19t) The title compound was obtained from suberic acid monomethyl ester (18b) and 5 methoxy-3-[2-(1-piperazinyl)ethyl]-lH-indole (16b) using Method L, yield 89%. 1 H NMR (CDCl3, HMDSO), 6: 1.18-1.78(m, 8H); 2.34(t, J=7.0 Hz, 4H); 2.52(t, J=6.0 Hz, 4H); 2.65 15 2.89(m, 4H); 3.38-3.74(m, 4H); 3.67(s, 3H); 3.85(s, 3H); 6.87(dd, J=8.8 and 3.0 Hz, 1H); 7.03(t, J= 3.0 Hz, 2H); 7.25(d, J=8.8 Hz, 1H); 8.01(s, 1H). Example 120 Ethyl 8-{4-[2-(1-benzothiophen-3-yl)acetyl]-1l-piperazinyl}-8-oxooctanoate (19u) 20 The title compound was obtained from suberic acid monoethyl ester (18c) and 2-(1 benzothiophen-3-yl)-1-(1-piperazinyl)-1-ethanone (13e) using Method L, yield 83%. 1 H NMR (CDC3, HMDSO), 6: 1.23(t, J=7.0 Hz, 3H); 1.16-1.87(m, 8H); 2.29(t, J=7.0 Hz, 4H); 3.27-3.83(m, 8H); 3.94(s, 2H); 4.12(q, J=7.0 Hz, 2H); 7.18-7.52(m, 2H); 7.72-7.96(m, 2H). 25 Example 121 Ethyl 7-[4-(3,4-dichlorophenyl)-1l-piperazinyl]-7-oxoheptanoate (19y) The title compound was obtained from pimelic acid monoethyl ester (18a) and 1-(3,4 30 dichlorophenyl)piperazine (17i) (commercially available) using Method L, yield 73%. 1 H NMR (CDCI 3 , HMDSO), 6: 1.23(t, J=7.0 Hz, 3H); 1.14-1.87(m, 6H); 2.16-2.49(m, 4H); 2.98-3.23(m, 4H); 3.47-3.83(m, 4H); 4.09(q, J=7.0 Hz, 2H); 6.74(dd, J=8.8 and 3.0 Hz, 1H); 6.96(d, J= 3.0 Hz, 1H); 7.32(d, J=8.8 Hz, 1H).
WO 03/082288 PCT/GB03/01463 - 162 Example 122 Ethyl 7-[4-(4-fluorophenyl)-1l-piperazinyl]-7-oxoheptanoate (19v) The title compound was obtained from pimelic acid monoethyl ester (18a) and 1-(4 5 fluorophenyl)piperazine (17J) (commercially available) using Method L, yield 74%. 1H NMR (CDCI 3 , HMDSO), 6: 1.22(t, J=7.0 Hz, 3H); 1.16-1.89(m, 6H); 2.16-2.49(m, 4H); 2.93-3.18(m, 4H); 3.49-3.87(m, 4H); 4.09(q, J=7.0 Hz, 2H); 6.77-7.14(m, 4H). Example 123 10 Ethyl 7-[4-(4-chlorophenyl)-1l-piperazinyl]-7-oxoheptanoate (19w) The title compound was obtained from pimelic acid monoethyl ester (18a) and 1-(4 chlorophenyl)piperazine (17k) (commercially available) using Method L, yield 75%. 1 H NMR (CDCI 3 , HMDSO), 65: 1.23(t, J=7.0 Hz, 3H); 1.16-1.87(m, 6H); 2.16-2.49(m, 4H); 15 3.00-3.21(m, 4H); 3.49-3.87(m, 4H); 4.11(q, J=7.0 Hz, 2H); 6.85(d, J=8.8 Hz, 2H); 7.23(d, J=8.8 Hz, 2H). Method M - Synthesis of O-Benzylhydroxamate Esters 20 To a solution of dicarbonic acid monoethyl (or monomethyl) ester 18a-c (2.75 mmol) in anhydrous dichloromethane (10 mL) oxalyl chloride (0.84 mL, 9.63 mmol) and a drop of dimethylformamide were added, and the resulting mixture was stirred for 30 minutes at room temperature followed by 1 hour at 40 0 C. The solution was carefully evaporated under reduced pressure and the residue was dried in vacuum at 40 0 C. The resulting 25 chloride was dissolved in anhydrous tetrahydrofuran (3 mL) and the obtained solution to a cold suspension (ice bath) of benzylhydroxylamine hydrochloride (2.75 mmol), tetrahydrofuran (10 mL), and saturated NaHCO 3 (10 mL) was added under vigorous stirring. The stirring was continued for 1 hour at ice bath temperature and 20 hours at room temperature. The mixture was diluted with brine (30 mL) and extracted with ethyl 30 acetate (3 x 25 mL). The organic phase was washed with brine and dried (Na 2
SO
4 ). The solvent was evaporated and the residue was chromatographed on silica gel (20 g) with chloroform - ethyl acetate (gradient from 100:0 to 50:50) as eluent to give the corresponding reaction product (20a-c) in 80-90% yield.
WO 03/082288 PCT/GB03/01463 -163 Example 124 Ethyl 7-[(benzyloxy)amino]-7-oxoheptanoate (20a) The title product was obtained from heptanedioic acid monoethyl ester, using Method M. 5 1 H NMR (CDCl 3 , HMDSO), 5: 1.22(t, J=7.0 Hz, 3H); 1.07-1.88(m, 6H); 1.89-2.26(m, 2H); 2.29(t, J=7.0 Hz, 2H); 4.11(q, J=7.0 Hz, 2H); 4.88(s, 2H); 7.31(s, 5H). Example 125 Methyl 8-[(benzyloxy)amino]-8-oxooctanoate (20b) 10 The title product was obtained from octanedioic acid monomethyl ester, using Method M. 1 H NMR (CDC13, HMDSO), 5: 1.09-1.83(m, 8H); 1.87-2.27(m, 2H); 2.27(t, J=7.0 Hz, 2H); 3.63(s, 3H); 4.87(s, 2H); 7.29(s, 5H). 15 Example 126 Ethyl 8-[(benzyloxy)amino]-8-oxooctanoate (20c) The title product was obtained from octanedioic acid monoethyl ester, using Method M. 1 H NMR (CDCl 3 , HMDSO), 5: 1.23(t, J=7.0 Hz, 3H); 1.09-1.83(m, 8H); 1.87-2.27(m, 2H); 20 2.27(t, J=7.0 Hz, 2H); 4.12(q, J=7.0 Hz, 2H); 4.87(s, 2H); 7.29(s, 5H). Method N - Synthesis of O-Benzvlhydroxamate Carboxylic Acids To a solution of appropriate ester 20a-c (1,5-2 mmol) in tetrahydrofuran (5 mL), a 25 saturated aqueous solution of LiOH (5 mL) was added. The mixture was stirred for 5 hours at room temperature. The organic volatiles were evaporated under reduced pressure and the mixture was supplemented with water (20 mL). The mixture was washed with diethyl ether and aqueous phase was acidified with 2 M HCI to pH 3. The crude product was extracted with ethyl acetate (3 x 20 mL). The organic layer was 30 washed with brine (3 x 10 mL) and dried (Na 2
SO
4 ). The solvent was evaporated and the residue was dried in vacuum to give expected product 21a or 21b in 60-70% yield.
WO 03/082288 PCT/GB03/01463 - 164 Example 127 7-[(Benzyloxy)amino]-7-oxoheptanoic acid (21a), The title product was obtained from ethyl 7-[(benzyloxy)amino]-7-oxoheptanoate (20a), 5 using Method N. 1 H NMR (CDCI 3 , HMDSO), 5: 1.07-1.88(m, 6H); 1.89-2.26(m, 2H); 2.29(t, J=7.0 Hz, 2H); 4.88(s, 2H); 7.32(s, 5H). Example 128 8-[(Benzyloxy)amino]-8-oxooctanoic acid (21b), 10 The title product was obtained from methyl 8-[(benzyloxy)amino]-8-oxooctanoate (20b) or ethyl 8-[(benzyloxy)amino]-8-oxooctanoate (20c), using Method N. 1 H NMR (CDC 3 , HMDSO), 5: 1.09-1.81(m, 8H); 1.88-2.29(m, 2H); 2.27(t, J=7.0 Hz, 2H); 4.86(s, 2H); 7.30(s, 5H). 15 Method P - General Synthesis of O-Benzyl Hydroxamates A solution of dicarbonic acid N-benzyloxy monoamide 21a or 21 b (1 eq) in anhydrous dimethylformamide (2 mL/mmol) was cooled in ice bath under argon atmosphere, and 20 carbonyldiimidazole (1.1 eq.) was added. The mixture was stirred at ice bath temperature for 30 minutes and a solution of appropriate piperazine (1 eq) in dimethylformamide (2 mL/mmol) was added (if the piperazine was used in a hydrochloride form, triethylamine (3 eq) was added to the reaction mixture prior to the piperazine hydrochloride). The mixture was stirred at ice bath temperature for 1 hour followed by 20 hours at room temperature. 25 Then the reaction mixture was diluted with brine and extracted with ethyl acetate. The organic phase was washed with brine, dried (Na 2
SO
4 ), and the solvent was evaporated. The residue was chromatographed on silica gel with appropriate eluent (chloroform - ethyl acetate for less polar and ethyl acetate - methanol for more polar compounds) to give the corresponding reaction product 22a-k. 30 Example 129 N-(Benzyloxy)-8-[4-(4-cyanobenzoyl)-1l-piperazinyl]-8-oxooctanamide (22a) The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoic acid (21b) and 35 4-(1-piperazinylcarbonyl)benzonitrile (13J), using Method P, yield 79%. 1 H NMR (CDCI 3
,
WO 03/082288 PCT/GB03/01463 -165 HMDSO), 5: 1.09-1.81(m, 8H); 1.87-2.17(m, 2H); 2.18-2.42(m, 2H); 3.32-3.69(m, 8H); 4.89(s, 2H); 7.38(s, 5H); 7.52(d, J=8.8 Hz, 2H); 7.76(d, J=8.8 Hz, 2H); 8.03(s, 1 H). Example 130 5 N-(Benzyloxy)-7-oxo-7-[4-(2-pyridinyl)-1l-piperazinyl]heptanamide (22b) The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoic acid (21a) and 1-(2-pyridinyl)piperazine (171) (commercially available), using Method P, yield 50%. 1 H NMR (CDCl 3 , HMDSO), 6: 1.16-1.81(m, 6H); 2.36(t, J=7.0 Hz, 2H); 3.21(q, J=6.0 Hz, 10 2H); 3.36-3.85(m, 8H); 4.76(bs, 1H); 5.09(s, 2H); 6.58-6.74(m, 2H); 7.34(s, 5H); 7.41 7.63(m, 1H); 8.12-8.29(m, 1H). Example 131 N-(Benzyloxy)-8-(4-{2-[4-(dimethylamino)phenyl]acetyl}-1-piperazinyl)-8-oxooctanamide 15 (22c) The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoic acid (21b) and 2-[4-(dimethylamino)phenyl]-1l-(1-piperazinyl)-1l-ethanone (13k), using Method P, yield 68%. 1 H NMR (CDCI 3 , HMDSO), 5: 1.05-1.81(m, 8H); 1.85-2.32(m, 4H); 2.89(s, 6H); 3.07 20 3.69(m, 8H); 3.65(s, 2H); 4.87(s, 2H); 6.67(d, J=8.8 Hz, 2H); 7.07(d, J=8.8 Hz, 2H); 7.36(s, 5H); 8.00(s, 1H). Example 132 N-(Benzyloxy)-8-oxo-8-[4-(2-pyrimidinyl)-1l-piperazinyl]octanamide (22d) 25 The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoic acid (21b) and 2-(1-piperazinyl)pyrimidine (17m) (commercially available), using Method P, yield 64%. IH NMR (CDCl 3 , HMDSO), 5: 1.14-1.81(m, 8H); 1.96-2.25(m, 2H); 2.36(t, J=7.0 Hz, 2H); 3.43-3.94(m, 8H); 4.89(s, 2H); 6.54(t, J=5.0 Hz, 1H); 7.38(s, 5H); 7.92-8.03(m, 1H); 30 8.32(d, J=5.0 Hz, 2H).
WO 03/082288 PCT/GB03/01463 - 166 Example 133 N-(Benzyloxy)-8-(4-{3-[3-(dimethylamino)phenyl]propyl}-1-piperazinyl)-8-oxooctanamide (22e) 5 The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoic acid (21 b) and N,N-dimethyl-3-[3-(1-piperazinyl)propyl]aniline (16k), using Method P, yield 63%. IH NMR
(CDCI
3 , HMDSO), 6: 1.18-1.83(m, 8H); 2.07-2.38(m, 4H); 2.43-2.76(m, 8H); 2.92(s, 6H); 3.38-3.80(m, 4H); 4.92(s, 2H); 6.71(d, J=8.8 Hz, 2H); 7.12(d, J=8.8 Hz, 2H); 7.41(s, 5H); 8.07-8.36(m, 1 H). 10 Example 134 N-(Benzyloxy)-8-{4-[2-(2-naphthyloxy)acetyl]-1l-piperazinyl}-8-oxooctanamide (22f) The title compound was obtained from 8-[(benzyloxy)amino]-8-oxooctanoic acid (21b) and 15 2-(2-naphthyloxy)-1-(1-piperazinyl)-1-ethanone (13c), using Method P, yield 66%. 'H NMR (CDCI 3 , HMDSO), 5: 1.14-1.76(m, 8H); 1.94-2.40(m, 4H); 3.29-3.74(m, 8H); 4.83(s, 2H); 4.88(s, 2H); 7.07-7.30(m, 3H); 7.36(s, 5H); 7.31-7.58(m, 1H); 7.65-7.92(m, 3H); 8.25(bs, 1 H). 20 Example 135 N-(Benzyloxy)-7-{4-[3-(1H-indol-3-yl)propanoyl]-1l-piperazinyl}-7-oxoheptanamide (22g) The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoic acid (21a) and 3-(1H-indol-3-yl)-1-(1-piperazinyl)-1-propanone (13f), using Method P, yield 63%. 1 H 25 NMR (CDCI 3 , HMDSO), 6: 1.09-1.85(m, 6H); 1.92-2.41(m, 4H); 2.58-3.00(m, 4H); 3.05 3.72(m, 8H); 4.89(s, 2H); 6.91-7.39(m, 5H); 7.38(s, 5H); 7.52-7.74(m, IH); 8.25-8.76(m, 1 H). Example 136 30 N-(Benzyloxy)-7-[4-(1 H-indol-3-ylcarbonyl)-1l-piperazinyl]-7-oxoheptanamide (22h) The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoic acid (21 a) and 1H-indol-3-yl(1-piperazinyl)methanone (13g), using Method P, yield 69%. 1 H NMR
(CDC
3 , HMDSO), 6: 1.14-1.78(m, 6H); 1.87-2.45(m, 4H); 3.34-3.78(m, 8H); 4.87(s, 2H); 35 7.14-7.54(m, 5H); 7.41(s, 5H); 7.58-7.83(m, 1H); 9.14-9.38(m, 1H).
WO 03/082288 PCT/GB03/01463 -167 Example 137 N-(Benzyloxy)-7-{4-[3-(1 H-indol-3-yl)propyl]-1l-piperazinyl}-7-oxoheptanamide (22i) The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoic acid (21a) 5 and 3-[3-(1-piperazinyl)propyl]-1H-indole (6f), using Method P, yield 87%. 1 H NMR (CDCl3, HMDSO), 6: 1.14-2.00(m, 8H); 2.12-2.56(m, 8H); 2.67-2.96(m, 4H); 3.32-3.71(m, 4H); 4.89(s, 2H); 6.92-7.36(m, 5H); 7.38(s, 5H); 7.49-7.69(m, 1H); 7.85-8.00(m, 1H). Example 138 10 N-(Benzyloxy)-7-[4-(1 H-indol-3-ylmethyl)-1l-piperazinyl]-7-oxoheptanamide (22j) The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoic acid (21a) and 3-(1-piperazinylmethyl)-IH-indole (16g), using Method P, yield 59%. 1 H NMR (CDC3, HMDSO), 6: 1.16-1.87(m, 6H); 2.03-2.60(m, 8H); 3.32-3.69(m, 4H); 3.72(s, 2H); 4.89(s, 15 2H); 7.05-7.34(m, 5H); 7.38(s, 5H); 7.60-7.85(m, 1H); 8.03-8.41(m, 1H). Example 139 N-(Benzyloxy)-7-[4-(3,4-dimethylphenyl)-1l-piperazinyl]-7-oxoheptanamide (22k) 20 The title compound was obtained from 7-[(benzyloxy)amino]-7-oxoheptanoic acid (21a) and 1-(3,4-dimethylphenyl)piperazine (17n) (commercially available), using Method P, yield 71%. 1 H NMR (CDC3, HMDSO), 5: 1.14-1.80(m, 6H); 2.11(s, 3H) 2.16(s, 3H); 2.36 2.49(m, 4H); 3.36-3.85(m, 8H); 4.89(s, 2H); 6.70(dd, J=8.8 and 3.0 Hz, 1H); 6.86(d, J= 3.0 Hz, 1H); 7.02(d, J=8.8 Hz, 1H), 7.34(s, 5H). 25 Method Q - General Synthesis of Hydroxamic Acids from Amidoesters To a 1 M solution of hydroxylamine hydrochloride in methanol (5 mL, 5 mmol) a 5 M solution of sodium methylate (1 mL, 5 mmol) was added, and the precipitate was filtered 30 off. To the filtrate, a solution of appropriate amidoester (19a-e) (2.47 mmol) in methanol (3 mL) was added and the resultant mixture was stirred at room temperature for 24 hours. The mixture was acidified with acetic acid to pH 5 and the solvent was evaporated. The residue was extracted with ethyl acetate (50 mL), the extract was washed with water, brine, and dried (MgSO 4 ). The extract was filtrated, concentrated to ca. 5-10 mL, and 35 allowed to crystallize. The precipitate was filtered, washed with ethyl acetate, and dried in vacuum to give the corresponding hydroxamic acid.
WO 03/082288 PCT/GB03/01463 -168 Example 140 8-Oxo-8-(4-phenyl-piperazin-1 -yl)-octanoic acid hydroxyamide (PX117402) 5 The title compound was obtained from 8-oxo-8-(4-phenyl-piperazin-1-yl)-octanoic acid methyl ester (19a) by Method Q, yield 42%. M.p. 134-136 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 6: 1.16-1.38 (m, 4H); 1.38-1.60 (m, 4H); 1.93 (t, 2H, J=7.4 Hz); 2.33 (t, 2H, J=7.2 Hz); 3.09 (m, 4H); 3.57 (m, 4H); 6.80 (t, 1H, J=7.1 Hz); 6.94 (d, 2H, J=8.0 Hz); 7.22 (t, 2H, J=7.7 Hz); 8.66 (s, 1H); 10.33 (s, 1H). HPLC analysis on Symmetry C8 column: 10 impurities 1.3% (column size 3.9 x 150 mm; mobile phase acetonitrile-0.1% H 3
PO
4 , 30:70; detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.1 mL/min). Anal. Calcd for C 18
H
27
N
3 0 3 , %: C 64.84, H 8.16, N 12.60. Found, %: C 64.71, H 8.20, N 12.52. Example 141 15 7-(4-Benzhydryl-piperazin-1 -yl)-7-oxo-heptanoic acid hydroxyamide (PX117403) The title compound was obtained from ethyl 7-(4-benzhydryl-1l-piperazinyl)-7 oxoheptanoate (19b) by Method Q, yield 29%. M.p. 157-1590C. 'H NMR (DMSO-d 6 , HMDSO) 6:1.08-1.32 (m, 2H); 1.35-1.60 (m, 4H); 1.82-2.02 (m, 2H); 2.03-2.40 (m, 6H); 20 3.23-3.60 (m, 4H overlapped with a water signal of DMSO); 4.30 (s, 1 H); 7.09-7.52 (m, 10 H); 8.68 (s, 1H); 10.34 (s, 1H). HPLC analysis on Zorbax Rx-C 1 8 column: impurities 1.5% (column size 4.6 x 150 mm; mobile phase acetonitrile-water, 80:20; detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C 24
H
31
N
3 0 3 , %: C 70.39, H 7.63, N 10.26. Found, %: C 70.09, H 7.67, N 10.11. 25 Example 142 7-Oxo-7-(4-phenyl-piperazin-1-yl)-heptanoic acid hydroxyamide (PX117404) The title compound was obtained from ethyl 7-oxo-7-(4-phenyl-1-piperazinyl)heptanoate 30 (19c) by Method Q, yield 27%. M.p. 107-109-C. 1 H NMR (DMSO-d 6 , HMDSO) 5: 1.15 1.36 (m, 2H); 1.38-1.60 (m, 4H); 1.93 (t, 2H, J=7.1 Hz); 2.33 (t, 2H, J=7.3 Hz); 3.09 (m, 4H); 3.58 (m, 4H); 6.80 (t, 1H, J=7.3 Hz); 6.95 (d, 2H, J=8.2 Hz); 7.22 (t, 2H, J=7.9 Hz); 8.69 (s, 1H); 10.35 (s, 1H). HPLC analysis on Zorbax SB-C 8 column: impurities 3% (column size 4.6 x 150 mm; mobile phase methanol-0.1% H 3
PO
4 , gradient from 50:50 to 35 90:10; detector UV 220 nm; sample concentration 0.55 mg/ml; flow rate 1.5 mL/min).
WO 03/082288 PCT/GB03/01463 - 169 Anal. Calcd for C 1 7
H
25
N
3 0 3 , %: C 63.93, H 7.89, N 13.16. Found, %: C 63.80, H 7.89, N 13.06. Example 143 5 8-(4-Benzhydryl-piperazin-1 -yl)-8-oxo-heptanoic acid hydroxyamide (PX1 17764) The title compound was obtained from methyl 8-(4-benzhydryl-1-piperazinyl)-8 oxooctanoate (19d) by Method Q, yield 32%. M.p. 126-129 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 6:1.14-1.30 (m, 4H); 1.34-1.54 (m, 4H); 1.91 (t, 2H, J=7.3 Hz); 2.15-2.32 (m, 10 6H); 3.38-3.50 (m, 4H); 4.30 (s, 1H); 7.17-7.50 (m, 10H); 8.66 (s, 1H); 10.32 (s, 1H). HPLC analysis on Symmetry C8 column: impurities 3.3% (column size 3.9 x 150 mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), 50:50; detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C 25
H
33
N
3 03, %: C 70.89, H 7.85, N 9.92. Found, %: C70.81, H 7.63, N 10.11. 15 Example 144 8-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-8-oxo-octanoic acid hydroxyamide (PX117768) The title compound was obtained from methyl 8-[4-(2-methoxyphenyl)-1l-piperazinyl]-8 20 oxooctanoate (19e) by Method Q, yield 34%. M.p. 135-1370C. 1 H NMR (DMSO-d 6 , HMDSO), 6:1.18-1.38 (mn, 4H); 1.38-1.60 (m, 4H); 1.93 (t, 2H, J=7.3 Hz); 2.31 (t, 2H, J=7.2 Hz); 2.82-2.98 (m, 4H); 3.50-3.62 (m, 4H); 3.78 (s, 3H); 6.84-7.02 (m, 4H); 8.66 (s, 1H); 10.33 (s, 1H). HPLC analysis on Symmetry C8 column: impurities <1.0% (column size 3.9 x 150 mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), 30:70; 25 detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.1 mL/min). Anal. Calcd for C 19
H
29
N
3 0 4 , %: C 62.79, H 8.04, N 11.56. Found, %: C62.71, H 8.07, N 11.64. Method R - General Synthesis of Hydroxamic Acids from Amidoesters 30 To a solution of amidoester 19f-w (1 mmol) in methanol (3-5 mL), a solution of hydroxylamine hydrochloride (0.278 g, 4 mmol) in methanol (3 mL) followed by a solution of NaOH (0.320 g, 8 mmol) in water (1 mL) were added. After stirring for 15-45 minutes at ambient temperature, the reaction mixture was diluted with brine and extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with brine, evaporated under 35 reduced pressure by adding benzene to remove traces of water several times, and dried WO 03/082288 PCT/GB03/01463 - 170 in vacuum. The crude product was crystallized or chromatographed on silica gel to give the corresponding hydroxamic acid. Example 145 5 8-[4-(2-Chloro-phenyl)-piperazin-1 -yl]-8-oxo octanoic acid hydroxyamide (PX1 18791) The title compound was obtained from methyl ethyl 8-[4-(2-chlorophenyl)-1-piperazinyl]-8 oxooctanoate (19f) using Method R. The crude product was crystallized from acetonitrile, yield 65%. M.p. 131-132 0 C. 'H NMR (DMSO-de, HMDSO), 6: 1.18-1.37(m, 4H); 1.40 10 1.60(m, 4H); 1.93(t, J=7.0 Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 2.83-3.20(m, 4H); 3.53-3.66(m, 4H); 7.06(dt, J=1.6 and 7.8 Hz, 1H); 7.15(dd, J=1.4 and 8.2 Hz, 1H); 7.30(dt, J=1.4 and 8.2 Hz, 1H); 7.43(dd, J=1.6 and 7.8 Hz, 1H); 8.66(s, 1H); 10.33(s, 1H). HPLC analysis on Omnispher 5 Ca column: impurities <1% (column size 4.6 x 150 mm; mobile phase 45% acetonitrile + 55% 0.1M phosphate buffer (pH 2.5); detector UV 254 nm; sample 15 concentration 1.0 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C 1 8
H
26
CIN
3 0 3 * 0.4H 2 0, %: C 57.64, H 7.20, N 11.20. Found, %: C 57.72, H 7.03, N 11.24. Example 146 8-[4-(3-Chloro-phenyl)-piperazin-1-yl]-8-oxo octanoic acid hydroxyamide (PX1 18792) 20 The title compound was obtained from ethyl 8-[4-(3-chlorophenyl)-1-piperazinyl]-8 oxooctanoate (19g) using Method R. The crude product was crystallized from acetonitrile, yield 56%. M.p. 122-124°C. 'H NMR (DMSO-de, HMDSO), 6: 1.19-1.38(m, 4H); 1.40 1.61(m, 4H); 1.93(t, J=7.2 Hz, 2H); 2.29(t, J=7.4 Hz, 2H); 2.80-3.20(m, 4H); 3.55-3.66(m, 25 4H); 6.81(d, J=7.8 Hz, 1H); 6.87-6.99(m, 2H); 7.22(t, J=7.8 Hz, 1H); 8.65(d, J=1.4 Hz, 1H); 10.33(s, 1H). HPLC analysis on Zorbax SB C 1 8 column: impurities -2.5% (column size 4.6 x 150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), gradient from 30:70 to 100:0; detector UV 254 nm; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C18H 26
CIN
3 0 3 , %: C 58.77, H 7.12, N 11.42. Found, %: C 58.41, 30 H 7.07, N 11.44. Example 147 7-[4-(2-Chloro-phenyl)-piperazin-1-yl]-7-oxo heptanoic acid hydroxyamide (PX1 18793) 35 The title compound was obtained from ethyl 7-[4-(2-chlorophenyl)-1-piperazinyl]-7 oxoheptanoate (19h) using Method R. The crude product was crystallized from WO 03/082288 PCT/GB03/01463 -171 acetonitrile, yield 62%. M.p. 128-1300C. 1 H NMR (DMSO-d 6 , HMDSO), 6: 1.17-1.36(m, 2H); 1.41-1.62(m, 4H); 1.94(t, J=7.0 Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 2.80-3.20(m, 4H); 3.54-3.67(m, 4H); 7.06(dt, J=1.6 and 7.8 Hz, 1H); 7.15(dd, J=1.8 and 8.0 Hz, 1H); 7.30(dt, J=1.8 and 8.0 Hz, 1H); 7.43(dd, J=1.6 and 7.8 Hz, 1H); 8.67(d, J=1.8 Hz, 1H); 10.33(s, 5 1 H). HPLC analysis on Omnispher 5 C18 column: impurities -1.8% (column size 4.6 x 150 mm; mobile phase 40% acetonitrile + 60% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C
1 7
H
24
CIN
3 0 3 , %: C 57.70, H 6.84, N 11.88. Found, %: C 57.76, H 6.87, N 11.79. 10 Example 148 7-[4-(3-Chloro-phenyl)-piperazin-1-yl]-7-oxo heptanoic acid hydroxyamide (PX1 18794) The title compound was obtained from ethyl 7-[4-(3-chlorophenyl)-1l-piperazinyl]-7 oxoheptanoate (191) using Method R. The crude product was crystallized from 15 acetonitrile, yield 48%. M.p. 120-1220C. 'H NMR (DMSO-d 6 , HMDSO), 6: 1.17-1.34(m, 2H); 1.40-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.32(t, J=7.3 Hz, 2H); 3.07-3.24(m, 4H); 3.47-3.67(m, 4H); 6.80(dd, J=1.5 and 8.0 Hz, 1H); 6.86-6.98(m, 2H); 7.22(t, J= 7.8 Hz, 1H); 8.65(d, J=1.8 Hz, 1H); 10.33(s, 1H). HPLC analysis on Zorbax SB C18 column: impurities -3% (column size 4.6 x 150 mm; mobile phase acetonitrile-0.1M phosphate 20 buffer (pH 2.5), gradient from 30:70 to 100:0; detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C 1 7
H
24
CIN
3 0 3 , %: C 57.70, H 6.84, N 11.88. Found, %: C 57.74, H 6.86, N 11.79. Example 149 25 8-[4-(Naphthalene-2-carbonyl)-piperazin-1-yl]-8-oxo octanoic acid hydroxyamide (PX118830) The title compound was obtained from ethyl 8-[4-(2-naphthoyl)-1-piperazinyl]-8 oxooctanoate (19j) using Method R. The crude product was crystallized from acetonitrile, 30 yield 54%. M.p. 133.5-134.5 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 6: 1.20-1.60(m, 8H); 1.92(t, J=7.2 Hz, 2H); 2.20-2.40(m, 2H); 3.28-3.76(m, 8H); 7.50-7.66(m, 3H); 7.94-8.10(m, 4H); 8.66(d, J=1.6 Hz, 1H); 10.32(s, 1H). HPLC analysis on Alltima C 8 column: impurities 3% (column size 4.6 x 150 mm; mobile phase 40% acetonitrile + 60% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min). 35 Anal. Calcd for C 2 3
H
29
N
3 0 4 , %: C 67.13, H 7.10, N 10.21. Found, %: C 66.90, H 7.09, N 10.23.
WO 03/082288 PCT/GB03/01463 - 172 Example 150 8-(4-Benzoyl-piperazin-1-yl)-8-oxo octanoic acid hydroxyamide (PX1 18831) 5 The title compound was obtained from ethyl 8-(4-benzoyl-1-piperazinyl)-8-oxooctanoate (19k) using Method R. The crude product was crystallized from acetonitrile, yield 29%. M.p. 100-110C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 1.18-1.36(m, 4H); 1.38-1.58(m, 4H); 1.92(t, J=7.4 Hz, 2H); 2.30(t, J=6.6 Hz, 2H); 3.49(m, 8H); 7.38-7.50(m, 5H); 8.66(s, 1H); 10.32(s, 1H). HPLC analysis on Alltima C18 column: impurities 2.5% (column size 4.6 x 10 150 mm; mobile phase 20% acetonitrile + 80% 0.1M phosphate buffer (pH 2.5); detector UV 254 nm; sample concentration 1.0 mg/ml; flow rate 1.7 mL/min). Anal. Calcd for C 1H 27
N
3 0 4 * 0.35 H 2 0, %: C 62.06, H 7.59, N 11.43. Found, %: C 62.03, H 7.50, N 11.33. 15 Example 151 8-[4-(4-Dimethylamino-benzoyl-piperazin-1-yl]-8-oxo octanoic acid hydroxyamide (PX1 18832) The title compound was obtained from ethyl 8-{4-[4-(dimethylamino)benzoyl]-1 20 piperazinyl}-8-oxooctanoate (191) using Method R. The crude product was crystallized from acetonitrile, yield 74%. M.p. 90-920C. 'H NMR (DMSO-da, HMDSO), 6: 1.18-1.30(m, 4H); 1.40-1.60(m, 4H); 1.93(t, J=7.2 Hz, 2H); 2.30(t, J=7.0 Hz, 2H); 2.95(s, 6H); 3.44 3.52(m, 8H); 6.70(d, J=8.6 Hz, 2H); 7.29(d, J=8.6 Hz, 2H); 8.64(s, 1 H); 10.32(s, 1H). HPLC analysis on Zorbax SB C18 column: impurities ~10% (column size 4.6 x 150 mm; 25 mobile phase gradient 15 min 10% acetonitrile/90% 0.1M phosphate buffer (pH 2.5) 100% 0.1M phosphate buffer; detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C 21
H
32
N
4 0 4 * 0.5 H 2 0, %: C 61.00, H 8.04, N 13.55. Found, %: C 60.98, H 7.85, N 13.37. 30 Example 152 8-[4-(4-Methoxyphenyl)-piperazin-1 -yl]-8-oxo octanoic acid hydroxyamide (PX1 18846) The title compound was obtained from ethyl 8-[4-(4-methoxyphenyl)-1-piperazinyl]-8 oxooctanoate I 9m) using Method R. The crude product was crystallized from 35 acetonitrile, yield 48%. M.p. 149-150oC. 'H NMR (DMSO-d 6 , HMDSO), 5: 1.18-1.33(m, 4H); 1.39-1.58(m, 4H); 1.93(t, J=7.2 Hz, 2H); 2.32(t, J=7.4 Hz, 2H); 2.88-3.03(m, 4H); WO 03/082288 PCT/GB03/01463 -173 3.52-3.61(m, 4H); 3.68(s, 3H); 6.83(dt, J=9.6 and 2.8 Hz, 2H); 6.90(dt, J=9.6 and 2.8 Hz, 2H); 8.64(s, 1H); 10.32(s, 1 H). HPLC analysis on Alltima C 1 8 column: impurities 1.5% (column size 4.6 x 150 mm; mobile phase 25% acetonitrile + 75% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). 5 Anal. Calcd for C 19
H
29
N
3 0 4 , %: C 62.79, H 8.04, N 11.56. Found, %: C 62.65, H 8.09, N 11.53. Example 153 8-[4-(3-Methoxyphenyl)-piperazin-1 -yl]-8-oxo octanoic acid hydroxyamide (PX1 18847) 10 The title compound was obtained from ethyl 8-[4-(3-methoxyphenyl)-1l-piperazinyl]-8 oxooctanoate (19n) using Method R. The crude product was crystallized from acetonitrile, yield 69%. M.p. 122-122.5 0 C. 'H NMR (DMSO-d 6 , HMDSO), 6: 1.18-1.36(m, 4H); 1.39 1.58(m, 4H);1.93(t, J=7.0 Hz, 2H); 2.32(t, J=7.6 Hz, 2H); 3.03-3.17(m, 4H); 3.50-3.63(m, 15 4H); 3.71(s, 3H); 6.39(dd, J=8.0 and 2.0 Hz, 1H); 6.46(t, J=2.0 Hz, 1H); 6.52(dd, J=8.0 and 2.0 Hz, 1H); 7.12(t, J=8.0 Hz, 1H); 8.63(d, J=1.6 Hz, 1H); 10.31(s, 1H). HPLC analysis on Alltima C 1 8 column: impurities 1% (column size 4.6 x 150 mm; mobile phase 25% acetonitrile + 75% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C 19
H
29
N
3 0 4 , %: C 62.79, H 20 8.04, N 11.56. Found, %: C 62.65, H 8.06, N 11.43. Example 154 N-Hydroxy-8-[4-(4-nitrophenyl)-1l-piperazinyl]-8-oxooctanamide (PX1 18849) 25 The title compound was obtained from ethyl 8-[4-(4-nitrophenyl)-1-piperazinyl]-8 oxooctanoate (19o) using Method R. The crude product was crystallized from acetonitrile, yield 31%. M.p. 125-127 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 6:1.20-1.28 (m, 4H); 1.33 1.50(m, 4H); 1.93(t, J=7.6 Hz, 2H); 2.33(t, J=7.2 Hz, 2H); 3.40-3.70(m, 8H); 7.00(d, J=9.0 Hz, 2H); 8.07(d, J=9.0 Hz, 2H); 8.67(s, 1H); 10.33(s, 1H). HPLC analysis on Alltima C18 30 column: impurities 2.5% (column size 4.6 x 150 mm; mobile phase 40% acetonitrile + 60% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C 1 8
H
26
N
4 0 5 , %: C 57.13, H 6.93, N 14.80. Found, %: C 57.06, H 6.94, N 14.72.
WO 03/082288 PCT/GB03/01463 -174 Example 155 N-Hydroxy-8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1-piperazinyl}-8-oxooctanamide (PX118927) 5 The title compound was obtained from methyl 8-{4-[2-(5-methoxy-1H-indol-3-yl)acetyl]-1 piperazinyl}-8-oxooctanoate (19) using Method R. The crude product was chromatographed on reverse phase Silasorb CL18 with methanol - 0.1% H 3
PO
4 as eluent. The eluate was evaporated, the residue was dissolved in ethyl acetate, the extract was washed with water, evaporated, and dried. Yield 35%. Foam. 'H NMR (DMSO-d 6 , 10 HMDSO), 6: 1.13-1.32(m, 4H); 1.34-1.55(m, 4H); 1.91(t, J=7.3 Hz, 2H); 2.17-2.31(m, 2H); 3.24-3.57(m, 8H, overlapped with a signal of water); 3.73(s, 3H); 3.75(s, 2H); 6.71(dd, J=8.8 and 2.4 Hz, 1H); 7.05(d, J=2.4 Hz, 1H); 7.16(br s, 1H); 7.22(d, J=8.8 Hz, 1H); 8.67(s, 1H); 10.33(s, 1H); 10.75(s, 1H). HPLC analysis on Kromasil C 18 column: impurities 5% (column size 4.6 x 150 mm; mobile phase 20% acetonitrile + 80% 0.2M acetate buffer 15 (pH 5.0); detector UV 230 nm; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C 23
H
32
N
4 0 5 * 0.25 H 2 0, containing 4% of inorganic impurities, %: C 59.06, H 7.00, N 11.98. Found, %: C 59.01, H 7.02, N 11.97. Example 156 20 N-Hydroxy-8-{4-[2-(2-naphthyloxy)ethyl]-1l-piperazinyl}-8-oxooctanamide (PX1 18930) The title compound was obtained from methyl 8-{4-[2-(2-naphthyloxy)ethyl]-1-piperazinyl} 8-oxooctanoate (19r) using Method R. The crude product was precipitated from diethyl ether, yield 35%. Foam. 1H NMR (DMSO-d 6 , HMDSO), 6: 1.16-1.31(m, 4H); 1.37-1.54(m, 25 4H); 1.93(t, J=7.2 Hz, 2H); 2.27(t, J=7.4 Hz, 2H); 2.41-2.55(m, 4H, overlapped with a signal of DMSO); 2.79(t, J=5.9 Hz, 2H); 3.39-3.49(m, 4H); 4.21(t, J=5.9 Hz, 2H); 7.16(dd, J=8.8 and 2.4 Hz, 1 H); 7.29-7.50(m, 3H); 7.76-7.86(m, 3H); 8.67(s, 1H); 10.33(s, 1H). HPLC analysis on AIItima C18 column: impurities 1% (column size 4.6 x 150 mm; mobile phase 25% acetonitrile + 75% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; 30 sample concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C 24
H
33
N
3 0 4 * 1.25
H
2 0, %: C 64.05, H 7.95, N 9.34. Found, %: C 64.17, H 7.91, N 9.28.
WO 03/082288 PCT/GB03/01463 - 175 Example 157 N-Hydroxy-8-{4-[2-(1 -naphthyloxy)acetyl]-1-piperazinyl}-8-oxooctanamide (PX118931) The title compound was obtained from ethyl 8-{4-[2-(1-naphthyloxy)acetyl]-1l-piperazinyl} 5 8-oxooctanoate (19s) using Method R. The crude product was precipitated from diethyl ether, yield 34%. Foam. 1 H NMR (DMSO-d 6 , HMDSO), 5: 1.14-1.33(m, 4H); 1.37-1.56(m, 4H); 1.92(t, J=7.0 Hz, 2H); 2.21-2.36(m, 2H); 3.22-3.61(m, 8H, overlapped with a signal of
H
2 0); 3.92(s, 2H); 7.34-7.57(m, 3H); 7.80-7.95(m, 4H); 8.66(s, 1H); 10.32(s, 1H). HPLC analysis on Alltima C 1 8 column: impurities 1% (column size 4.6 x 150 mm; mobile phase 10 50% acetonitrile + 50% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C 24
H
31
N
3 0s, %: C 65.29, H 7.08, N 9.52. Found, %: C 65.15, H 7.45, N 9.40. Example 158 15 N-Hydroxy-8-{4-[2-(5-methoxy-1 H-indol-3-yl)ethyl]-1 -piperazinyl}-8-oxooctanamide oxalate (PX118932) The title compound was obtained from methyl 8-{4-[2-(5-methoxy-1H-indol-3-yl)ethyl]-1 piperazinyl}-8-oxooctanoate (19t) using Method R. The crude product (ca. 0.33 mmol) 20 was dissolved in abs. ethanol (1.5 mL) and a solution of oxalic acid dihydrate (0.1 g, 0.79 mmol) in abs. ethanol (1 mL) was added. The reaction mixture was stirred for 2 hours at ambient temperature, the precipitate was filtered and washed with diethyl ether. The product was crystallized from ethanol and dried, yield 70%. M.p. 122-125 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 1.17-1.35(m, 4H); 1.39-1.57(m, 4H); 1.93(t, J=7.6 Hz, 2H); 2.32(t, 25 J=7.4 Hz, 2H); 2.93-3.17(m, 8H); 3.56-3.72(m, 4H); 3.77(s, 3H); 6.73(dd, J=8.8 and 2.2 Hz, 1H); 7.03(d, J=2.2 Hz, 1H); 7.16(d, J=2.2 Hz, 1H); 7.23(d, J=8.8 Hz, 2H); 10.35(s, 1H); 10.75(s, 1H). HPLC analysis on Zorbax SB C18 column: impurities -7% (column size 4.6 x 150 mm; mobile phase 15 min gradient: acetonitrile-0.1M phosphate buffer (pH 2.5); 30/70 -100/0; detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.5 30 mL/min). Anal. Calcd for C 2 3
H
3 4
N
4 0 4 * 1.3 (COOH) 2 , %: C 56.15, H 6.74, N 10.23. Found, %: C 56.00, H 6.86, N 10.12.
WO 03/082288 PCT/GB03/01463 - 176 Example 159 8-{4-[2-(1-Benzothiophen-3-yl)acetyl]-1 -piperazinyl}-N-hydroxy-8-oxooctanamide (PX118967) 5 The title compound was obtained from ethyl 8-{4-[2-(1-benzothiophen-3-yl)acetyl]-1 piperazinyl}-8-oxooctanoate (19u) using Method R. The crude product was crystallized from acetonitrile, yield 35%. M.p. 140-141oC. 1H NMR (DMSO-d 6 , HMDSO), 6:1.15 1.34(m, 4H); 1.37-1.56(m, 4H); 1.92(t, J=7.3 Hz, 2H); 2.29(t, J=7.3 Hz, 2H); 3.36-3.60(m, 8H); 3.98(s, 2H); 7.34-7.44(m, 2H); 7.51(s, 1H); 7.78-7.85(m, 1H); 7.93-8.05(m, 1H); 10 8.65(s, 1H); 10.32(s, 1H). HPLC analysis on Omnispher 5 C18 column: impurities 1% (column size 4.6 x 150 mm; mobile phase 50% acetonitrile + 50% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C 22
H
2 9
N
3 0 4 S, %: C 61.23, H 6.77, N 9.74. Found, %: C 60.76, H 6.71, N 9.82. 15 Example 160 7-[4-(3,4-Dichlorophenyl)-1 -piperazinyl]-N-hydroxy-7-oxoheptanamide (PX118989) The title compound was obtained from ethyl 7-[4-(3,4-dichlorophenyl)-1-piperazinyl]-7 20 oxoheptanoate (19y) using Method R. The crude product was crystallized from ethyl acetate- methanol (9:1), yield 43%. M.p. 125-1260C. 'H NMR (DMSO-de, HMDSO), 6: 1.14-1.34(m, 2H); 1.38-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.32(t, J=7.0 Hz, 2H); 3.07 3.26(m, 4H); 3.48-3.63(m, 4H); 6.94(dd, J=8.8 and 2.9 Hz, 1H); 7.14(d, J=2.9 Hz, 1H); 7.40(d, J=8.8 Hz, 1H); 8.67(d, J=1.5 Hz, 1H); 10.33(s, 1H). HPLC analysis on Omnispher 25 5 C18 column: impurities 1% (column size 4.6 x 150 mm; mobile phase 40% acetonitrile + 60% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C17H 23 C1 2
N
3 0 3 , %: C 52.59, H 5.97, N 10.82. Found, %: C 52.50, H 5.90, N 10.75. 30 Example 161 7-[4-(4-Fluorophenyl)-1-piperazinyl]-N-hydroxy-7-oxoheptanamide (PX118990) The title compound was obtained from ethyl 7-[4-(4-fluorophenyl)-1-piperazinyl]-7 oxoheptanoate (19v) using Method R. The crude product was crystallized from ethyl 35 acetate - methanol (9:1), yield 29%. M.p. 119-12000. 1H NMR (DMSO-d 6 , HMDSO), 6: 1.18-1.34(m, 2H); 1.39-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.32(t, J=7.3 Hz, 2H); 2.94- WO 03/082288 PCT/GB03/01463 - 177 3.11(m, 4H); 3.51-3.62(m, 4H); 6.92-7.13(m, 4H); 8.67(s, 1H); 10.33(s, 1H). HPLC analysis on Alitima C 18 column: impurities 2% (column size 4.6 x 150 mm; mobile phase 35% acetonitrile + 65% 0.1M phosphate buffer (pH 2.5); detector UV 254 nm; sample concentration 1.0 mg/ml; flow rate 1.0 mLfmin). Anal. Calcd for C 1 7
H
24
FN
3 0 3 , %: C 60.52, 5 H 7.17, N 12.45. Found, %: C 60.42, H 7.22, N 12.32. Example 162 7-[4-(4-Chlorophenyl)- 1-piperazinyl]-N-hydroxy-7-oxoheptanamide (PX118991) 10 The title compound was obtained from ethyl 7-[4-(4-chlorophenyl)-1-piperazinyl]-7 oxoheptanoate (19w) using Method R. The crude product was crystallized from ethyl acetate - methanol (9:1), yield 21%. M.p. 119-121oC. 'H NMR (DMSO-do, HMDSO), 6: 1.19-1.34(m, 2H); 1.39-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 3.01 3.18(m, 4H); 3.50-3.64(m, 4H); 6.95(d, J=8.8 Hz, 2H); 7.24(d, J=8.8 Hz, 2H); 8.67(s, 1H); 15 10.33(s, 1H). HPLC analysis on Omnispher 5 C18 column: impurities 2.2% (column size 4.6 x 150 mm; mobile phase 35% acetonitrile + 65% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C 17
H
24
CIN
3 0 3 , %: C 57.70, H 6.84, N 11.88. Found, %: C 57.75, H 6.84, N 11.80. 20 Method S - General Synthesis of Hydroxamic Acids from O-benzvl Hydroxamates To a solution of O-benzylhydroxamate 22a-k (1 mmol) in methanol (5-10 mL), 5% palladium on activated carbon catalyst (0.050 g) was added and the black suspension was vigorously stirred under hydrogen atmosphere until initial compound disappeared. 25 The reaction mixture was filtered through a small amount of silica gel (ca. 1-2 cm thin layer), the sorbent was washed with methanol, and the filtrate was evaporated in vacuum. The crude product was crystallized or chromatographed on silica gel to give the corresponding hydroxamic acid. 30 Example 163 8-[4-(4-Cyanobenzoyl)-piperazin-1-yl]-8-oxo octanoic acid hydroxyamide (PX118844) The title compound was obtained from N-(benzyloxy)-8-[4-(4-cyanobenzoyl)-l piperazinyl]-8-oxooctanamide (22a), using Method S, yield 74%. M.p. 150-150.50C. 1 H 35 NMR (DMSO-d 6 , HMDSO), 6: 1.18-1.38(m, 4H); 1.40-1.60(m, 4H); 1.92(t, J=7.0 Hz, 2H); 2.22-2.40(m, 2H); 3.20-3.70(m, overlapped with a signal of H 2 0); 7.61 (d, J=8.0 Hz, 2H); WO 03/082288 PCT/GB03/01463 - 178 7.94(d, J=8.0 Hz, 2H); 8.64(s, 1H); 10.32(s, 1H). HPLC analysis on Omnispher 5 C1a column: impurities 2% (column size 4.6 x 150 mm; mobile phase 20% acetonitrile + 80% 0.1M phosphate buffer (pH 2.5); detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C 2 0
H
26
N
4 0 4 * 0.5 H 2 0, %: C 60.74, H 6.88, N 14.17. 5 Found, %: C 60.83, H 6.82, N 13.88. Example 164 7-Oxo-7-(4-pyridin-2-yl-piperazin-1 -yl]-heptanoic acid hydroxyamide oxalate (PX118845) 10 The title compound was obtained from N-(benzyloxy)-7-oxo-7-[4-(2-pyridinyl)-l piperazinyl]heptanamide (22b), using Method S. The crude product (ca. 0.33 mmol) was dissolved in abs. ethanol (1.5 mL) and a solution of oxalic acid dihydrate (0.1 g, 0.79 mmol) in abs. ethanol (1 mL) was added. The reaction mixture was stirred for 2 hours at ambient temperature, the precipitate was filtered and washed with diethyl ether. The 15 product was crystallized from ethanol and dried, yield 65%. M.p. 118-122-C. 'H NMR (DMSO-d 6 , HMDSO), 5: 1.20-1.40(m, 2H); 1.42-1.65(m, 4H); 2.35(t, J=7.2 Hz, 2H); 2.77(t, J=7.2 Hz, 2H); 3.37-3.63(m, 8H); 6.65(dd, J=7.2 and 5.0 Hz, 1H); 6.83(d, J= 8.2 Hz, 1H); 7.55(ddd, J=8.2, 7.2 and 1.8 Hz, 1H); 8.11(dd, J= 5.0 and 1.8 Hz, 1H). HPLC analysis on Ultra Aqueous C,8 column: impurities 2.3% (column size 4.6 x 150 mm; mobile phase 5% 20 acetonitrile + 95% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.5 mglmL; flow rate 1.5 mL/min). Anal. Calcd for C 16
H
24
N
4 0 3 * 0.5 C 2
H
2 0 4 * 0.5 H 2 0, %: C 54.53, H 7.00, N 14.96. Found, %: C 54.43, H 7.20, N 14.84. Example 165 25 8-(4-{2-[4-(Dimethylamino)phenyl]acetyl}-1 -piperazinyl)-N-hydroxy-8-oxooctanamide (PXI 18848) The title compound was obtained from N-(benzyloxy)-8-(4-{2-[4 (dimethylamino)phenyl]acetyl}-1l-piperazinyl)-8-oxooctanamide (22c), using Method S. 30 The crude product was precipitated from diethyl ether, yield 63%. M.p. 77-79 0 C. 1 H NMR (DMSO-d 6 , HMDSO), 6: 1.18-1.34(m, 4H); 1.36-1.56(m, 4H); 1.92(t, J=7.2 Hz, 2H); 2.27(t, J=7.2 Hz, 2H); 2.85(s 6H); 3.25-3.50(m, 8H, overlapped with a signal of H 2 0); 3.58(s, 2H); 6.66(d, J=8.2, 2H); 7.03(d, J=8.2 Hz, 2H); 8.65(s, 1H); 10.32(s, 1H). HPLC analysis on Alltima C18 column: impurities 4% (column size 4.6 x 150 mm; mobile phase 15% 35 acetonitrile + 85% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample WO 03/082288 PCT/GB03/01463 -179 concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C 22
H
34
N
4 0 4 * 0.5H 2 0, %: C 61.80, H 8.25, N 13.10. Found, %: C 61.90, H 8.18, N 13.11. Example 166 5 N-Hydroxy-8-oxo-8-[4-(2-pyrimidinyl)-1l-piperazinyl]octanamide (PX1 18850) The title compound was obtained from N-(benzyloxy)-8-oxo-8-[4-(2-pyrimidinyl)-1 piperazinyl]octanamide (22d), using Method S. The crude product was crystallized from methanol, yield 37%. M.p. 132-133.50C. 'H NMR (DMSO-d 6 , HMDSO), 6: 1.18-1.36(m, 10 4H); 1.38-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.33(t, J=7.3 Hz, 2H); 3.46-3.58(m, 4H); 3.62-3.80(m, 4H); 6.65(t, J=4.8 Hz, 1H); 8.37(d, J=4.8 Hz, 2H); 8.65(br s, 1H); 10.29(br s, 1H). HPLC analysis on Alltima C18 column: impurities 1% (column size 4.6 x 150 mm; mobile phase 20% acetonitrile + 80% 0.1M phosphate buffer (pH 2.5); detector UV 230 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C1 6
H
25
N
5 0 3 , 15 %: C 57.30, H 7.51, N 20.88. Found, %: C 57.23, H 7.58, N 20.80. Example 167 8-{4-[4-(Dimethylamino)phenethyl]-1l-piperazinyl}-N-hydroxy-8-oxooctanamide (PXI 18928) 20 The title compound was obtained from N-(benzyloxy)-8-(4-{3-[3 (dimethylamino)phenyl]propyl}-1l-piperazinyl)-8-oxooctanamide (22e), using Method S. The crude product was crystallized from acetonitrile, yield 45%. M.p. 103-1050C. 'H NMR (DMSO-d6, HMDSO), 6: 1.11-1.33(m, 4H); 1.35-1.54(m, 4H); 1.92(t, J=7.2 Hz, 2H); 2.26(t, 25 J=7.4 Hz, 2H); 2.24-2.66(m, 8H, partially overlapped with a signal of DMSO); 2.83(s, 6H); 3.25-3.50(m, 4H, partially overlapped with a signal of water); 6.64(d, J=8.6 Hz, 2H); 7.00(d, J=8.6 Hz, 2H); 8.67(s, 1 H); 10.33(s, 1H). HPLC analysis on AIItima C18 column: impurities 1% (column size 4.6 x 150 mm; mobile phase 8% acetonitrile + 92% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 1.0 mg/ml; flow 30 rate 1.3 mL/min). Anal. Calcd for C 22
H
36
N
4 0 3 , containing 1% of inorganic impurities, %: C 64.66, H 8.88, N 13.71. Found, %: C 64.64, H 8.94, N 13.70.
WO 03/082288 PCT/GB03/01463 -180 Example 168 N-Hydroxy-8-{4-[2-(2-naphthyloxy)acetyl]-1l-piperazinyl}-8-oxooctanamide (PX1 18929) The title compound was obtained from N-(benzyloxy)-8-{4-[2-(2-naphthyloxy)acetyl]-1 5 piperazinyl}-8-oxooctanamide (22f), using Method S. The crude product was crystallized from acetonitrile, yield 45%. M.p. 139-140.5oC. 1 H NMR (DMSO-d 6 , HMDSO), 5: 1.17 1.35(m, 4H); 1.37-1.56(m, 4H); 1.93(t, J=7.2 Hz, 2H); 2.32(t, J=7.0 Hz, 2H); 3.39-3.60(m, 8H, overlapped with a signal of H 2 0); 4.97(s, 2H); 7.17-7.51(m, 4H); 7.37-7.89(m, 3H); 8.67(s, 1H); 10.34(s, 1 H). TLC: single spot at Rf 0.3 (ethyl acetate-methanol, 4:1; 10 detection - UV-254 nm). Anal. Calcd for C 24
H
3 1
N
3 0 5 , containing 1% of inorganic impurities, %: C 64.64, H 7.01, N 9.42. Found, %: C 64.64, H 6.96, N 9.45. Example 169 N-Hydroxy-7-{4-[3-(1H-indol-3-yl)propanoyl]-1l-piperazinyl}-7-oxoheptanamide 15 (PX118968) The title compound was obtained from N-(benzyloxy)-7-{4-[3-(1H-indol-3-yl)propanoyl]-1 piperazinyl}-7-oxoheptanamide (2_2g), using Method S. The crude product was crystallized from methanol - ethyl acetate (1:2), yield 40%. M.p. 152.5-153.50C. 1 H NMR 20 (DMSO-d 6 , HMDSO), 65: 1.13-1.33(m, 2H); 1.36-1.57(m, 4H); 1.92(t, J=7.0 Hz, 2H); 2.27(t, J=7.0 Hz, 2H); 2.67(t, J=7.3 Hz, 2H); 2.93(t, J=7.3 Hz, 2H); 3.25-3.52(m, 8H, overlapped with a signal of H 2 0); 6.96(t, J=7.3 Hz, 1H); 7.05(t, J=7.3 Hz, 1H); 7.14(d, J=2.0 Hz, 1H); 7.33(d, J=7.3 Hz, 1H); 7.51(d, J=7.3 Hz, 1H); 8.67(s, 1H); 10.34(s, 1H); 10.78(s, 1H). HPLC analysis on Alltima C 1 8 column: impurities 1% (column size 4.6 x 150 mm; mobile 25 phase 20% acetonitrile + 80% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.25 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C 22
H
30
N
4 0 4 * 0.5
H
2 0 * 0.1 EtOAc, %: C 62.59, H 7.42, N 12.81. Found, %: C 62.61, H 7.35, N 12.92. Example 170 30 N-Hydroxy-7-[4-(1 H-indol-3-ylcarbonyl)-1l-piperazinyl]-7-oxoheptanamide (PX118969) The title compound was obtained from N-(benzyloxy)-7-[4-(1H-indol-3-ylcarbonyl)-1 piperazinyl]-7-oxoheptanamide (22h), using Method S. The crude product was crystallized from methanol - ethyl acetate (2:3), yield 52%. M.p. 86-88 0 C. 1 H NMR (DMSO-d 6 , 35 HMDSO), 5: 1.16-1.35(m, 2H); 1.39-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.32(t, J=7.3 Hz, 2H); 3.43-3.70(m, 8H); 7.04-7.21(m, 2H); 7.44(dd, J=7.3 and 1.5 Hz, 1H); 7.66-7.75(m, WO 03/082288 PCT/GB03/01463 - 181 2H); 8.67(s, 1 H); 10.34(s, 1H); 11.62(s, 1H). HPLC analysis on Omnispher 5 C18 column: impurities 2% (column size 4.6 x 150 mm; mobile phase 20% acetonitrile + 80% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for C 20
H
2 6
N
4 0 4 * 0.5 H 2 0 * 0.2 CH 2
CI
2 , containing 2% of 5 inorganic impurities, %: C 58.18, H 6.56, N 13.30. Found, %: C 58.12, H 6.54, N 13.33. Example 171 N-Hydroxy-7-{4-[3-(1H-indol-3-yl)propyl]-1l-piperazinyl}-7-oxoheptanamide (PX1 18970) 10 The title compound was obtained from N-(benzyloxy)-7-{4-[3-(1H-indol-3-yl)propyl]-1 piperazinyl}-7-oxoheptanamide (22i), using Method S. The crude product was crystallized from methanol - ethyl acetate (2:3), yield 23%. M.p. 165-166oC. 1 H NMR (DMSO-d 6 , HMDSO), 5: 1.11-1.32(m, 2H); 1.35-1.57(m, 4H); 1.79(t, J=7.3 Hz, 2H); 1.92(t, J=7.0 Hz, 2H); 2.18-2.41(m, 10H); 2.68(t, J=7.3 Hz, 2H); 3.42(br s, 4H); 6.90-7.06(m, 2H); 7.10(s, 15 1H); 7.31(d, J=7.3 Hz, 1H); 7.49(d, J=7.3 Hz, 1H); 8.66(s, 1H); 10.32(s, 1H); 10.74(s, 1H). HPLC analysis on ji Bondasphere Phenyl column: impurities 2.5% (column size 4.6 x 150 mm; mobile phase 20% acetonitrile + 80% 0.1 M phosphate buffer (pH 2.5); detector UV 210 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C
22
H
32
N
4 0 3 , %: C 65.97, H 8.05, N 13.99. Found, %: C 65.85, H 8.10, N 13.97. 20 Example 172 N-Hydroxy-7-[4-(1H-indol-3-ylmethyl)-1l-piperazinyl]-7-oxoheptanamide (PX1 18978) The title compound was obtained from N-(benzyloxy)-7-[4-(1H-indol-3-ylmethyl)-1 25 piperazinyl]-7-oxoheptanamide (221), using Method S. The crude product was crystallized from methanol - ethyl acetate (2:3), yield 52%. M.p. 65-67oC. 1 H NMR (DMSO-d 6 , HMDSO), 6: 1.10-1.30(m, 2H); 1.34-1.56(m, 4H); 1.91(t, J=7.3 Hz, 2H); 2.24(t, J=7.0 Hz, 2H); 2.23-2.50(m, 4H, overlapped with a signal of DMSO); 3.25-3.48(m, 4H, overlapped with a signal of water); 3.65(s, 2H); 6.97(t, J=7.3 Hz, 1H); 7.07(t, J=7.3 Hz, 1H); 7.23(s, 30 1H); 7.34(d, J=7.3 Hz, 1H); 7.63(d, J=7.3 Hz, 1H); 8.66(s, 1H); 10.32(s, 1H); 10.96(s, 1H). HPLC analysis on Omnispher C18 column: impurities 2% (column size 4.6 x 150 mm; mobile phase 15% acetonitrile + 85% 0.1M phosphate buffer (pH 2.5); detector UV 210 nm; sample concentration 0.5 mg/ml; flow rate 1.0 mL/min). Anal. Calcd for C 20
H
28
N
4 0 3 * 0.4 H 2 0 * 0.25 EtOAc, containing 4% of inorganic material, %: C 60.49, H 7.86, N 13.44. 35 Found, %: C 60.65, H 7.43, N 13.39.
WO 03/082288 PCT/GB03/01463 - 182 Example 173 7-[4-(3,4-Dimethylphenyl)-1l-piperazinyl]-N-hydroxy-7-oxoheptanamide (PX118994) The title compound was obtained from N-(benzyloxy)-7-[4-(3,4-dimethylphenyl)-1 5 piperazinyl]-7-oxoheptanamide (22k), using Method S. The crude product was crystallized from acetonitrile, yield 73%. M.p. 119.5-120.5°C. 1 H NMR (DMSO-d 6 , HMDSO), 5: 1.18-1.34(m, 2H); 1.39-1.59(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2.11(s, 3H); 2.16(s, 3H); 2.32(t, J=7.3 Hz, 2H); 2.93-3.09(m, 4H); 3.49-3.61(m, 4H); 6.66(dd, J=8.8 and 2.2 Hz, 1H); 6.76(d, J=2.2 Hz, 1H); 6.97(d, J=8.8 Hz, 1H); 8.67(d, J=1.5 Hz 1H); 10 10.34(s, 1H). HPLC analysis on Alltima C18 column: impurities <2% (column size 4.6 x 150 mm; mobile phase 25% acetonitrile + 75% 0.1M phosphate buffer (pH 2.5); detector UV 210 nm; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for
C,H
29
N
3 0 3 , %: C 65.68, H 8.41, N 12.09. Found, %: C 65.65, H 8.54, N 12.09. 15 Example 174 8-[4-(3-Fluorophenyl)-piperazin--yl]-8-oxooctanoic acid hydroxyamide (PX118859) The title compound was obtained using methods analogous to those described above. M.p. 149-150.5°C. 'H NMR (DMSO-de, HMDSO) 5: 1.19-1.37(m, 4H); 1.39-1.58(m, 4H); 20 1.93(t, J=7.5 Hz, 2H); 2.32(t, J=7.4 Hz, 2H); 2.88-3.04(m, 4H); 3.54-3.65(m, 4H); 6.93 7.22(m, 4H); 8.65(br s, IH); 10.32(s, IH). HPLC analysis on Alltima C18: -1% impurities (column size 4.6x150mm; mobile phase 35% acetonitrile + 65% 0.1M phosphate buffer (pH 2.5); detector UV 220nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd. for CIBH 26
FN
3 0 3 , %: C 61.52, H 7.46, N 11.96. Found, %: C 61.45, H 7.48, N 25 11.88 Example 175 8-Oxo-8-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-octanoic acid hydroxyamide (PX118860) 30 The title compound was obtained using methods analogous to those described above. M. p. 126-1280C. 'H NMR (DMSO-de, HMDSO) 5: 1.16-1.37(m, 4H); 1.38.1.59(m, 4H); 1.93(t, J=7.4 Hz, 2H); 2.33(t, J=7.0 Hz, 2H); 3.14.3.39(m, 4H, overlapped with a signal of water); 3.52-3.65(m, 4H); 7.09(d, J=7.6 Hz, IH); 7.18(s, IH); 7.22(d, J=8.4 Hz, IH); 7.43(t, 35 J=8.0 Hz, IH); 8.64(s, IH); 10.32(s, IH). HPLC analysis on Omnispher 5 C1 8 : <1% impurities (column size 4.6 x 150 mm; mobile phase 40% acetonitrile + 60% 0.1M WO 03/082288 PCT/GB03/01463 -183 phosphate buffer (pH 2.5); detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.5 mL/min). Anal. Calcd for C 19
H
26
F
3
N
3 0 3 , %: C 56.85, H 6.53, N 10.47. Found, %: C 56.62, H 6.48, N 10.40. 5 Example 176 8-{4-[Bis-(4-fluorophenyl)-methyl]-piperazin-1 -yl}-8-oxo octanoic acid hydroxyamide (PX118898) The title compound was obtained using methods analogous to those described above. 10 M.p. foam. 1 H NMR (DMSO-d 6 , HMDSO) 6: 1.16-1.35(m, 4H); 1.38-1.58(m, 4H); 1.91(t, J=7.4 Hz, 2H); 2.15-2.30(m, 6H); 3.52-3.65(m, 4H, overlapped with a signal of water); 4,39(s, 1H); 7.13(t, J=8.6 Hz, 4H); 7.44(dd, J=8.6 and 5.6 Hz, 4H); 8.65(br s, 1H); 10.31(br s, IH). HPLC analysis on Alltima C 1 8 : -3.5% impurities. (column size 4.6 x 150 mm; mobile phase 70% acetonitrile + 30% 0.1M phosphate buffer (pH 2.5); detector UV 15 220 nm; sample concentration 1.0 mg/ml; flow rate 1.3 mL/min). Anal. Calcd for
C
25
H
31
F
2
N
3 0 3 * 0.25 H 2 0, %: C 64.71, H 6.84, N 9.06. Found, %: C 64.50, H 6.81, N 8.90. Example 177 20 8-(3-Methyl-4-m-tolyl-piperazin-1 -yl)-8-oxo octanoic acid hydroxyamide (PXI 18899) The title compound was obtained using methods analogous to those described above. M.p. 75- 760C. 1 H NMR (DMSO-d 6 , HMDSO) 5: 0.82 and 0.90(d and d, J=6.6 Hz, 3H); 1.14-1.35(m, 4H); 1.39-1.59(m, 4H); 1.93(t, J=7.2 Hz, 2H); 2.24(s, 3H); 2. 13-2.42(m, 2H); 25 2.80-3.53(m, 5H, partly overlapped with a signal of H 2 0); 3.62-4.31(m, 2H); 6.59(d, J=7.8 Hz, 1H); 6.69(d, J=7.8 Hz, IH); 6.72(s, 1H); 7.09(t, J=7.8 Hz, 1H); 8.65(s, 1H); 10.32(s, 1H). HPLC analysis on Omnispher 5 C18: -1.8% impurities (column size 4.6 x 150 mm; mobile phase 30% acetonitrile + 70% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.2 mL/min). Anal. Calcd. for C 2 0
H
31
N
3 0 3 , 30 %: C 66.45, H 8.64, N 11.62. Found, %: C 66.43, H 8.67, N 11.52. Example 178 8-[4-(2-1 H-Indol-3-yl-acetyl)-piperazin--yl]-8-oxo octanoic acid hydroxyamide (PXI 18900) 35 The title compound was obtained using methods analogous to those described above. M.p. foam. 1 H NMR (DMSO-d 6 , HMDSO) 6: 1.10-1.31(m, 4H); 1.34-1.56(m, 4H); 1.93(t, WO 03/082288 PCT/GB03/01463 -184 J=7.2 Hz, 2H); 2.18-2.35(m, 2H); 3.20-3.58(m, 8H, overlapped with a signal of H 2 0); 3.79(s, 2H); 6.96(t, J=7.0 Hz, 1H); 7.07(t, J=7.0 Hz, 1H); 7.21(s, 1H); 7.34(d, J=7.8 Hz, 1H); 7.55(d, J=7.8 Hz, 1H); 8.65(s, 1H); 10.32(s, 1H); 10.93(s, 1H). HPLC analysis on Alltima C,8: -7.5% impurities (column size 4.6 x 150 mm; mobile phase 30% acetonitrile + 5 70% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.0 mL/min). Anal. Calcd. for C 2 2 H3oN 4 0 4 * 0.1H 2 0 *0.1EtOAc., containing 3% of inorganic impurities, %: C 61.39, H 7.13, N 12.78. Found, %: C 61.45, H 7.08, N 12.81. 10 Example 179 8-(4-Diphenylacetyl-piperazin--yl)-8-oxo octanoic acid hydroxyamide (PX118901) The title compound was obtained using methods analogous to those described above. M.p. foam. 1 H NMR (DMSO-d 6 , HMDSO) 6: 1.14-1.30(m, 4H); 1.34-1.54(m, 4H); 1.93(t, 15 J=7.2 Hz, 2H); 2.17-2.32(m, 2H); 3.09-3.21(m, 2H); 3.30-3.58(m, 6H, overlapped with a signal of H 2 0); 5.55(s, 1H); 7.15-7.37(m, 10H); 8.66(s, 1H); 0.33(s, IH). HPLC analysis on Omnispher 5 C18: -2.2% impurities. (column size 4.6 x 150 mm; mobile phase 60% acetonitrile + 40% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.2 mL/min.) Anal Calcd for C 26
H
33
N
3 0 4 * 0.5 MeOH, 20 %: C 68.07, H 7.54, N 8.99. Found, %: C 68.04, H 7.23, N 8.99. Example 180 8-[4-(2-Naphthalen-2-yl-acetyl)-piperazin--yl]-8-oxo octanoic acid hydroxyamide (PX118902) 25 The title compound was obtained using methods analogous to those described above. M. p. foam. 1 H NMR (DMSO-d 6 , HMDSO) 5: 1.12-1.32(m, 4H); 1.35-1.56(m, 4H); 1.92(t, J=7.4 Hz, 2H); 2.28(t, J=6.8 Hz, 2H); 3.26-3.58(m, 8H, overlapped with a signal of H 2 0); 3.91(s, 2H); 7.39(dd, J=8.4 and 1.8 Hz, 1H); 7.45-7.54(m, 2H); 7.73(s, 1H); 7.79-7.92(m, 30 3H); 8.67(s, 1H); 10.33(s, 1H). HPLC analysis on Alltima C18: -5% impurities (column size 4.6 x 150 mm;mobile phase 40% acetonitrile + 60% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 0.5 mg/ml; flow rate 1.3 mL/min.) Anal. Calcd. for C 24
H
31
N
3 0 4 * 0.75 H 2 0, %: C 65.66, H 7.46, N 9.57. Found, %: C 65.52, H 7.40, N 9.43. 35 WO 03/082288 PCT/GB03/01463 - 185 Example 181 8-{4-[4-(1-Hydroxyimino-ethyl)-phenyl]-piperazin-1-yl}-8-oxo octanoic acid hydroxyamide (PX118903) 5 The title compound was obtained using methods analogous to those described above. M.p. 147-147.5°C. 1 H NMR (DMSO-d 6 , HMDSO) 5: 1.18-1.35(m, 4H); 1.37-1.57(m, 4H); 1.93(t, J=7.4 Hz, 2H); 2.09(s, 3H); 2.33(t, J=7.2 Hz, 2H); 3.06-3.25(m, 4H); 3.51-3.65(m, 4H); 6.94(d, J=8.8 Hz, 2H); 7.51(d, J=8.8 Hz, 2H); 8.65(s, 1H); 10.32(s, IH); 10.86(s, 1H). HPLC analysis on Zorbax SB 5 C18: -5% of acetophenone derivative (sample contains ca. 10 5% of the corresponding methylketone 8-[4-(4-acetylphenyl)-1l-piperazinyl]-N-hydroxy-8 oxooctanamide). (column size 4.6 x 150 mm; mobile phase acetonitrile - 0.1M phosphate buffer (pH 2.5), gradient 15 min from 20:80 to 100:0; detector UV 254 nm; sample concentration 0.5 mg/ml; flow rate 1.0 mL/min.) Anal. Calcd. for C 20
H
3 oN 4 0 4 containing 5% of the acetophenone C 20
H
29
N
3 0 4 , %: C 61.63, H 7.75, N 14.20. Found, %: C 61.67, H 15 7.76, N 13.76. Example 182 8-Oxo-8[4-(3-phenylallyl)-piperazin-1 -yl]-octanoic acid hydroxyamide (PX118904) 20 The title compound was obtained using methods analogous to those described above. M. p. foam. 1 H NMR (DMSO-d 6 , HMDSO) 5: 1.14-1.32(m, 4H); 1.36-1.55(m, 4H); 1.93(t, J=7.3 Hz, 2H); 2. 19-2.45(m, 6H); 3.10(d, J=6.6 Hz, 2H); 3.27-3.51(m, 4H, overlapped with a signal of H 2 0); 6.29(dt, J=6.60 and 16.2 Hz, IH); 6.54(d, J=16.2 Hz, IH); 7. 15 7.48(m, 3H); 7.44(d, J=6.6 Hz, 2H); 8.67(br s, H); 10.33(s, IH). HPLC analysis on Alltima 25 C18: -5% impurities (column size 4.6 x 150 mm; mobile phase 20% acetonitrile + 80% 0.1M phosphate buffer (pH 2.5); detector UV 220 nm; sample concentration 1.0 mg/ml; flow rate 1.5 mL/min.) Anal. Calcd. for C21H 31
N
3 0 3 * 0.5 H 2 0, %: C 65.94, H 8.43, N 10.99. Found, %: C 66.05, H 8.28, N 10.94. 30 Example 183 8-[4-(2-Naphthalen-2-yl-ethyl)-piperazin-1 -yl]-8-oxo octanoic acid hydroxyamide (PX118908) The title compound was obtained using methods analogous to those described above. M. 35 p. 118-120'C. 1H NMR (DMSO-d 6 , HMDSO) 5: 1.16-1.34(m, 4H); 1.36-1.56(m, 4H); 1.92(t, J=7.3 Hz, 2H); 2.27(t, J=7.6 Hz, 2H); 2.34-2.55(m, 4H, overlapped with a signal of WO 03/082288 PCT/GB03/01463 - 186 DMSO); 2.63(t, J=8.4 Hz, 2H); 2.92(t, J=8.4 Hz, 2H); 3.28-3.52 (m, 4H, overlapped with a signal of H 2 0); 7.37-7.53(m, 3H); 7.73(s, 1H); 7.77-7.91(m, 3H); 8.67(s, 1H); 10.33(s, IH). HPLC analysis on Omnispher 5 C 1 8 : ~1.5% impurities (column size 4.6 x 150 mm; mobile phase 25% acetonitrile + 75% 0.1M phosphate buffer (pH 2.5); detector UV 220 5 nm; sample concentration 0.5 mg/ml; flow rate 1.2 mL/min.) Anal. Calcd. for C 24
H
33
N
3 0 3 , %: C 70.04, H 8.08, N 10.21. Found, %: C 69.31, H 8.11, N 10.20. Example 184 8-[4-(2,2-Diphenyl-ethyl)-piperazin-1 -yl]-8-oxo octanoic acid hydroxyamide (PXI 18909) 10 The title compound was obtained using methods analogous to those described above. M. p. 117-118°C. 1H NMR (DMSO-d6, HMDSO) 6: 1.12-1.31(m, 4H); 1.34-1.54(m, 4H); 1.91(t, J=7.4 Hz, 2H); 2.23(t, J=7.4 Hz, 2H); 2.31-2.48(m, 4H, overlapped with a signal of DMSO); 2.94(d, J=7.6 Hz, 2H); 3.26-3.48 (m, 4H, overlapped with a signal of H 2 0); 4.26(t, 15 J=7.6 Hz, 1H); 7.09-7.40(m, 10H); 8.65(s, 1H); 10.31(s, 1 H). HPLC analysis on Alltima C18: <1% impurities. (column size: 4.6 x 150 mm; mobile phase 25% acetonitrile + 75% 0.1M phosphate buffer (pH 2.5); detector UV 215 nm; sample concentration 1.0 mg/ml; flow rate 1.15 mL/min.) Anal. Calcd. for C 26
H
35
N
3 0 3 , %: C 71.37, H 8.06, N 9.60. Found, %: C 71.01, H 8.11, N 9.59. 20 Biological Activity Candidate compounds were assessed for their ability to inhibit deacetylase activity (biochemical assays) and to inhibit cell proliferation (cell-based antiproliferation assays), 25 as described below. Primary Assay (1): Deacetylase Activity Briefly, this assay relies on the release of radioactive acetate from a radioactively labelled 30 histone fragment by the action of HDAC enzyme. Test compounds, which inhibit HDAC, reduce the yield of radioactive acetate. Signal (e.g., scintillation counts) measured in the presence and absence of a test compound provide an indication of that compound's ability to inhibit HDAC activity. Decreased activity indicates increased inhibition by the test compound. 35 WO 03/082288 PCT/GB03/01463 -187 The histone fragment was an N-terminal sequence from histone H4, and it was labelled with radioactively labelled acetyl groups using tritiated acetylcoenzyme A (coA) in conjunction with an enzyme which is the histone acetyltransferase domain of the transcriptional coactivator p300. 0.33 mg of peptide H4 (the N-terminal 20 amino acids of 5 histone H4, synthesized using conventional methods) were incubated with His6-tagged p300 histone acetyltransferase domain (amino acids 1195-1673, expressed in E. coil strain BLR(DE3)pLysS (Novagen, Cat. No. 69451-3) and 3H-acetyl coA (10 pIL of 3.95 Ci/mmol; from Amersham) in a total volume of 300 pL of HAT buffer (50 mM TrisC pH 8, 5% glycerol, 50 mM KCI, 0.1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM 10 dithiothreitol (DTT) and 1 mM 4-(2-aminoethyl)-benzenesulfonylfluoride (AEBSF)). The mixture was incubated at 300C for 45 min after which the His-p300 was removed using nickel-trinitriloacetic acid agarose (Qiagen, Cat No. 30210). The acetylated peptide was then separated from free acetyl coA by size exclusion chromatography on Sephadex G 15 (Sigma G-15-120), using distilled H 2 0 as the mobile phase. 15 After purification of the radiolabelled histone fragment, it was incubated with a source of HDAC (e.g., an extract of HeLa cells (a rich source of HDAC), recombinantly produced HDAC1 or HDAC2) and any released acetate was extracted into an organic phase and quantitatively determined using scintillation counting. By including a test compound with 20 the source of HDAC, that compound's ability to inhibit the HDAC was determined. Primary Assay (2): Deacetylase Activity: Fluorescent Assay Alternatively, the activity of the compounds as HDAC inhibitors was determined using a 25 commercially available fluorescent assay kit: (Fluor de LysTM, BioMol Research Labs, Inc., Plymouth Meeting, USA). HeLa extract was incubated for 1 hour at 370C in assay buffer (25 mM HEPES, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCI 2 , pH 8.0) with 15 pM acetylated substrate in the presence of test compound (HDAC inhibitor). The extent of deacetylation was determined by the addition of 50 pL of a 1-in-500 dilution of Developer, and 30 measurement of the fluorescence (excitation 355 nm, emission 460 nm), according to the instructions provided with the kit. Extensive comparative studies have shown that Primary Assay (1) and Primary Assay (2), discussed above, yield equivalent results. Primary Assay results reported herein are (a) 35 exclusively from (1); (b) exclusively from (2); or (c) from both (1) and (2).
WO 03/082288 PCT/GB03/01463 - 188 HeLa Cell Extract The HeLa cell extract was made from HeLa cells (ATCC Ref. No. CCL-2) by freeze thawing three times in 60 mM TrisCI pH 8.0,450 mM NaCI, 30% glycerol. Two cell 5 volumes of extraction buffer were used, and particulate material was centrifuged out (20800 g, 4°C, 10 min). The supernatant extract having deacetylase activity was aliquotted and frozen for storage. Recombinantly Produced HDAC1 and HDAC2 10 Recombinant plasmids were prepared as follows. Full length human HDAC1 was cloned by PCR using a Agt 1I Jurkat cDNA library (Clontech-HL5012b). The amplified fragment was inserted into the EcoRI-Sall sites of 15 pFlag-CTC vector (Sigma-E5394), in frame with the Flag tag. A second PCR was carried out in order to amplify a fragment containing the HDAC1 sequence fused to the Flag tag. The resulting fragment was subcloned into the EcoRI-Sacl sites of the baculovirus transfer vector pAcHTL-C (Pharmingen-21466P). 20 Full length mouse HDAC2 was subcloned into pAcHLT-A baculovirus transfer vector (Pharmingen-21464P) by PCR amplification of the EcoRI-Sacl fragment from a HDAC2 pFlag-CTC construct. Recombinant protein expression and purification was performed as follows. 25 HDAC1 and HDAC2 recombinant baculoviruses were constructed using BaculoGold Transfection Kit (Pharmingen-554740). Transfer vectors were co-transfected into SF9 insect cells (Pharmingen-21300C). Amplification of recombinant viruses was performed according to the Pharmingen Instruction Manual. SF9 cells were maintained in serum 30 free SF900 medium (Gibco 10902-096). For protein production, 2x107 cells were infected with the appropriate recombinant virus for 3 days. Cells were then harvested and spun at 3,000 rpm for 5 minutes. They were then washed twice in PBS and resuspended in 2 pellet volumes of lysis buffer (25 mM 35 HEPES pH 7.9, 0.1 mM EDTA, 400 mM KCI, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Resuspended cells were frozen on dry ice and thawed at 370C 3 times and centrifuged for WO 03/082288 PCT/GB03/01463 -189 10 minutes at 14,000 rpm. The supernatant was collected and incubated with 300 pl of 50% Ni-NTA agarose bead slurry (Qiagen-30210). Incubation was carried out at 40C for 1 hour on a rotating wheel. The slurry was then centrifuged at 500 g for 5 minutes. Beads were washed twice in 1 ml of wash buffer (25 mM HEPES pH7.9, 0.1 mM EDTA, 150 mM 5 KCI, 10% glycerol, 0.1% NP-40, 1 mM AEBSF). Protein was eluted 3 times in 300 pl elution buffer (25 mM HEPES pH 7.9, 0.1 mM EDTA, 250 mM KCI, 10% glycerol, 0.1% NP-40, 1 mM AEBSF) containing increasing concentrations of imidazole: 0.2 M, 0.5 M and 1 M. Each elution was performed for 5 minutes at room temperature. Eluted protein was kept in 50% glycerol at -700C. 10 Assay Method A source of HDAC (e.g., 2 pL of crude HeLa extract, 5 pL of HDAC1 or HDAC2; in elution buffer, as above) was incubated with 3 pL of radioactively labelled peptide along with 15 appropriate dilutions of candidate compounds (1.5 pL) in a total volume of 150 pL of buffer (20 mM Tris pH 7.4, 10% glycerol). The reaction was carried out at 37 0 C for one hour, after which the reaction was stopped by adding 20 pL of 1 M HCI / 0.4 M sodium acetate. Then, 750 pL of ethyl acetate was added, the samples vortexed and, after centrifugation (14000 rpm, 5 min), 600 pL from the upper phase were transferred to a vial 20 containing 3 mL of scintillation liquid (UltimaGold, Packard, Cat. No. 6013329). Radioactivity was measured using a Tri-Carb 2100TR Liquid Scintillation Analyzer (Packard). Percent activity (% activity) for each test compound was calculated as: 25 % activity = { (Sc - B) / (So - B) } x 100 wherein Sc denotes signal measured in the presence of enzyme and the compound being tested, So denotes signal measured in the presence of enzyme but in the absence of the 30 compound being tested, and B denotes the background signal measured in the absence of both enzyme and compound being tested. The IC50 corresponds to the concentration which achieves 50% activity. IC50 data for several compounds of the present invention, as determined using this 35 assay, are also shown in Table 1, below.
WO 03/082288 PCT/GB03/01463 - 190 Measurement of cell viability in the presence of increasing concentration of test compound at different time points is used to assess both cytotoxicity and the effect of the compound on cell proliferation. 5 Secondary Assay: Cell Proliferation Compounds with HDAC inhibition activity, as determined using the primary assay, were subsequently evaluated using secondary cell-based assays. The following cell lines were used: 10 HeLa - Human cervical adenocarcinoma cell line (ATCC ref. No. CCL-2). K11 - HPV E7 transformed human keratinocyte line provided by Pidder Jansen-Duerr, Institut for Biomedizinische Alternsforschung, lnnsbruck, Austria. 15 NHEK-Ad - Primary human adult keratinocyte line (Cambrex Corp., East Rutherford, NJ, USA). JURKAT - Human T-cell line (ATCC no. TIB-152). 20 Assay Method Cells were cultured, exposed to candidate compounds, and incubated for a time, and the number of viable cells was then assessed using the Cell Proliferation Reagent WST-1 25 from Boehringer Mannheim (Cat. No. 1 644 807), described below. Cells were plated in 96-well plates at 3-1 0x103 cells/well in 100 pL of culture medium. The following day, different concentrations of candidate compounds were added and the cells incubated at 37 0 C for 48 h. Subsequently, 10 pL/well of WST-1 reagent was added and 30 the cells reincubated for 1 hour. After the incubation time, absorbance was measured. WST-1 is a tetrazolium salt which is cleaved to formazan dye by cellular enzymes. An expansion in the number of viable cells results in an increase in the overall activity of mitochondrial dehydrogenases in the sample. This augmentation in the enzyme activity 35 leads to an increase in the amount of formazan dye formed, which directly correlates to the number of metabolically active cells in the culture. The formazan dye produced is WO 03/082288 PCT/GB03/01463 - 191 quantified by a scanning multiwell spectrophotometer by measuring the absorbance of the dye solution at 450 nm wavelength (reference wavelength 690 nm). Percent activity (% activity) in reducing the number of viable cells was calculated for each 5 test compound as: % activity = { (Sc - B) / (S' - B) } x 100 wherein S c denotes signal measured in the presence of the compound being tested, So 10 denotes signal measured in the absence of the compound being tested, and B denotes the background signal measured in blank wells containing medium only. The IC50 corresponds to the concentration which achieves 50% activity. IC50 values were calculated using the software package Prism 3.0 (GraphPad Software Inc., San Diego, CA), setting top value at 100 and bottom value at 0. 15 IC50 data for several compounds of the present invention, as determined using this assay, are also shown in Table 2, below. Measurement of cell viability in the presence of increasing concentration of test 20 compound at different time points is used to assess both cytotoxicity and the effect of the compound on cell proliferation. Screening in Mice with Intraperitoneal P388 Tumour 25 Female B6D2F1 hybrid mice weighing 19-23 grams were inoculated with the tumour cell line P388 (106 cells in 0.2 mL) intraperitoneally (IP). Inoculation of tumour cells was performed on a Friday and treatment with compounds at a dose of 64 pmol/kg/day started on Day 3 (Monday). The compounds were given as a single daily IP dose for five consecutive days. Compounds were dissolved in DMSO, at a concentration 30 corresponding to 50 pL injection volume per treatment. Treatments were given at the same hour of the day (within one hour). Five mice in each group were treated with compounds, and with each series of experiments, control groups (not treated, and DMSO treated) were included. Moribund mice were euthanised, and the day of death was recorded. Log-rank analysis of the survival data was performed using the statistical 35 software SAS v8.1 (SAS Institute, Cary, NC, USA).
WO 03/082288 PCT/GB03/01463 -192 Biological Data IC50 (or percent activity) data for several compounds of the present invention, as determined using the assays described above are summarised in Table 1 and Table 2, 5 below. The results of in vivo studies of mice with intraperitoneal P388 tumour for several compounds of the present invention, using the methods described above, are summarised in Table 3. 10 Table 1 Biochemical Assay Data Compound HDAC Inhibition (IC50 unle ss otherwise specified) No. Ref. HeLa HDAC1 HDAC2 1 TSA 5nM 15nM 17nM 2 SAHA 189nM - 3 PX117403 28% @500 nM - 4 PX117404 35% @ 500 nM - 5 PX117764 785 nM - 6 PX117768 175 nM - 7 PX118490 59% @ 100 nM - 8 PX118491 47% @ 100 nM - 9 PX118807 60% @ 100nM 10 PX118810 46 nM 11 PX118811 42 nM 12 PX118812 26 nM - 13 PX118791 36nM -_ 14 PX118792 34 nM - 15 PX118793 188 nM 16 PX118794 74 nM - 17 PX118830 133 nM 18 PX118831 194 nM 19 PX118832 212 nM 20 PX118844 286 nM - 21 PX118846 3.4 nM - 22 PX118847 31 nM 23 PX118848 44% @100 nM - 24 PX118849 26 nM - 25 PX118850 70 nM - WO 03/082288 PCT/GB03/01463 -193 Table 2 Cell-Based Antiproliferation Assay Data Compound Cell Proliferation Inhibition WST-1 (IC50 unless otherwise specified) No. Ref. HeLa K11 NHEK-AD Jurkat TSA 350 nM 0.38 pM 0.2 pM 42 nM Oxamflatin - 4.82 pM 3.53 pM 170 nM MS-275 - 9.16 pM 3.1 pM 365 nM SAHA - 6.82 pM 5.37 pM 750 nM 1 PX117403
-
- 2 PX117404
-
-
3 PX117764 29.2 pM 9.45 pM - 2.68 pM 4 PX117768 3.30 pM 8.67 pM - 1.04 pM 5 PX118490 1.00 pM 2.49 pM - 460 nM 6 PX118491 18 pM 8.24 pM - 3.21 pM Table 3 In Vivo Studies of Mice with Intraperitoneal P388 Tumour Compound Log rank statistic Wilcoxon statistic No. of mice - 6.8173 1556.0 25 DMSO 6.4056 1290.0 20 PX118490 -3.3797 -654.0 5 PX118807 -4.6177 -750.0 5 PX118871 -3.4210 -605.0 5 PX118875 -3.0949 -525.0 5 PX118882 -4.9869 -613.0 5 PX118893 -3.5651 -725.0 5 PX118905 -4.0610 -565.0 5 PX118907 -4.1247 -817.0 5 PX118910 -9.6221 -869.0 5 5 The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the 10 art without departing from the scope of the present invention as set out in the appended claims.
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Claims (79)

1. A compound of the formula: O 1 1 / 2 21I Cy-Q-J! N 1 4N-J2Q C-N-OH (1) H wherein: Cy is independently a cyclyl group; 5 Q 1 is independently a covalent bond or cyclyl leader group; the piperazin-1,4-diyl group is optionally substituted; J 1 is independently a covalent bond or -C(=O)-; j 2 is independently -C(=O)- or -S(=0)2- ; Q 2 is independently an acid leader group; 10 wherein: Cy is independently: C 3 - 20 carbocyclyl, C 3 _ 20 heterocyclyl, or C5- 20 oaryl; 15 and is optionally substituted; Q 1 is independently: a covalent bond; C 1 7 alkylene; or C.l 7 alkylene-X-C1. 7 alkylene, -X-Cl. 7 alkylene, or C 1 . 7 alkylene-X-, 20 wherein X is -0- or -S-; and is optionally substituted; Q 2 is independently: C 4 -Balkylene; and is optionally substituted; 25 and has a backbone length of at least 4 atoms; or: Q 2 is independently: C 5 - 20 arylene; C5- 20 oarylene-Cl 7 alkylene; 30 Cl. 7 alkylene-Ce- 20 arylene; or, CI. 7 alkylene-Co- 2 0 arylene-Cl- 7 alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms; WO 03/082288 PCT/GBO3/01463 - 200 or a pharmaceutically acceptable salt, solvate, amide, ester, ether, chemically protected form, or prodrug thereof. 5
2. A compound according to claim 1, wherein the piperazin-1,4-diyl group is unsubstituted or substituted at one or more the 2-, 3-, 5-, and 6-positions with C 1 .4alkyl. 10 ***
3. A compound according to claim 1 or 2, wherein: J 1 is a covalent bond and J 2 is -C(=O)-; or: J 1 is -C(=O)- and J 2 is -C(=O)-; or: 15 J 1 is a covalent bond and J 2 is -S(=O) 2 -.
4. A compound according to claim 1 or 2, wherein: J 1 is a covalent bond; and j 2 is -C(=O)-. 20
5. A compound according to claim 1 or 2, wherein: J' is -C(=O)-; and J 2 is -C(=O)-.
6. A compound according to claim 1 or 2, wherein: J' is a covalent bond; and j 2 is -S(=O) 2 -. 25
7. A compound according to any one of claims 1 to 6, wherein Q 1 is independently: a covalent bond; or 30 a cyclyl leader group; and is optionally substituted. 35
8. A compound according to any one of claims 1 to 6, wherein Q 1 is independently a cyclyl leader group, and is optionally substituted. WO 03/082288 PCT/GB03/01463 -201
9. A compound according to any one of claims 1 to 6, wherein Q 1 is independently C 1 . 7 alkylene, and is optionally substituted. 5 10. A compound according to any one of claims 1 to 6, wherein: Q 1 is independently Cl. 7 alkylene, and is optionally substituted; J 1 is independently a covalent bond; J 2 is independently -C(=O)-.
10
11. A compound according to any one of claims 1 to 6, wherein: Q 1 is independently C 1 . 7 alkylene, and is optionally substituted; J 1 is independently -C(=O)-; J 2 is independently -C(=O)-. 15
12. A compound according to any one of claims 1 to 6, wherein: Q 1 is independently C 1 7 alkylene, and is optionally substituted; J 1 is independently a covalent bond; J 2 is independently -S(=0) 2 -. 20
13. A compound according to any one of claims 1 to 6, wherein: Q 1 is independently C4_ 7 alkylene, and is optionally substituted; J' is independently -C(=O)-; J 2 is independently -S(=O) 2 -. 25
14. A compound according to any one of claims 1 to 13, wherein Q' is independently C 1 . 3 alkylene, and is optionally substituted. 30
15. A compound according to any one of claims 1 to 6, wherein Q' is independently: CI. 7 alkylene-X-C 1 . 7 alkylene, -X-C 1 7 alkylene, or CI. 7 alkylene-X-; wherein X is -0- or -S-; and is optionally substituted. 35
16. A compound according to any one of claims 1 to 6, wherein Q 1 is independently: C 1 . 3 alkylene-X-C 1 . 3 salkylene, -X-C 1 ~ -3alkylene, or Cl 3 alkylene-X-; WO 03/082288 PCT/GB03/01463 - 202 wherein X is -0- or -S-; and is optionally substituted. 5
17. A compound according to any one of claims 1 to 16, wherein Q', if other than a covalent bond, is substituted.
18. A compound according to claim 17, wherein substituents on Q 1 , if present, are 10 independently: halo, hydroxy, ether, C5- 20 aryl, acyl, amino, amido, acylamido, or oxo.
19. A compound according to claim 17, wherein substituents on Q 1 , if present, are independently: -F, -CI, -Br, -I, -OH, -OMe, -OEt, -OPr, -Ph, -NH 2 , -CONH 2 , or =0. 15
20. A compound according to any one of claims 1 to 16, wherein Q', if other than a covalent bond, is unsubstituted. 20
21. A compound according to any one of claims 1 to 6, wherein Q 1 is independently a covalent bond.
22. A compound according to any one of claims 1 to 6, wherein: 25 Q 1 is independently a covalent bond; J' is independently a covalent bond; J 2 is independently -C(=O)-.
23. A compound according to any one of claims 1 to 6, wherein: 30 Q 1 is independently a covalent bond; J 1 is independently -C(=O)-; J 2 is independently -C(=O)-. WO 03/082288 PCT/GB03/01463 - 203
24. A compound according to any one of claims 1 to 6, wherein: Q 1 is independently a covalent bond; J' is independently a covalent bond; J 2 is independently -S(=O) 2 -. 5
25. A compound according to any one of claims 1 to 6, wherein: Q 1 is independently a covalent bond; J 1 is independently -C(=O)-; j 2 is independently -S(=0) 2 -. 10
26. A compound according to any one of claims 1 to 25, wherein Q 2 is independently: C 4 -8alkylene; 15 and is optionally substituted; and has a backbone length of at least 4 atoms.
27. A compound according to any one of claims 1 to 25, wherein Q 2 is independently a saturated C 4 .salkylene group. 20
28. A compound according to any one of claims 1 to 25, wherein Q 2 is independently a partially unsaturated C 4 -8alkylene group.
29. A compound according to any one of claims 1 to 25, wherein Q 2 is independently 25 an aliphatic C 4 -8alkylene group
30. A compound according to any one of claims 1 to 25, wherein Q 2 is independently a linear C 4 -8alkylene group. 30
31. A compound according to any one of claims 1 to 25, wherein Q 2 is independently a saturated aliphatic C 4 -8alkylene group.
32. A compound according to any one of claims 1 to 25, wherein Q 2 is independently a saturated linear C4-8alkylene group. 35 WO 03/082288 PCT/GB03/01463 - 204
33. A compound according to any one of claims 1 to 25, wherein Q 2 is independently a partially unsaturated aliphatic C4-8alkylene group.
34. A compound according to any one of claims 1 to 25, wherein Q 2 is independently a 5 partially unsaturated linear C4.- 8 alkylene group.
35. A compound according to any one of claims 1 to 25, wherein Q 2 is independently selected from: -(CH 2 ) 5 -; -(CH 2 ) 6 -; -(CH 2 ) 7 -; -(CH 2 ) 8 -; 10 -CH(CH 3 )CH 2 CH 2 CH 2 CH 2 -; -CH 2 CH 2 CH 2 CH 2 CH(CH 3 )-; -CH 2 CH 2 CH 2 CH=CH-; and, -CH 2 CH 2 CH 2 CH 2 CH=CH-. 15
36. A compound according to any one of claims 1 to 25, wherein Q 2 is independently selected from: -(CH 2 ) 5 ", -(CH 2 ) 6 -, -(CH 2 ) 7 -, and -(CH 2 ) 8 -. 20
37. A compound according to any one of claims 1 to 25, wherein Q 2 , is independently: C5- 20 arylene; C5- 20 arylene-C 1 7 alkylene; C 1 . 7 alkylene-C 5 - 20 arylene; 25 C _ 7 alkylene-C5- 20 arylene-C. 7 alkylene; or, and is optionally substituted; and has a backbone length of at least 4 atoms.
38. A compound according to any one of claims 1 to 25, wherein Q 2 , is independently: 30 0 5 C- 20 arylene; and is optionally substituted; and has a backbone length of at least 4 atoms.
39. A compound according to any one of claims 1 to 25, wherein Q 2 , is independently: 35 C5- 20 oarylene-C 1 .- 7alkylene; C 17 alkylene-Cs- 20 arylene; WO 03/082288 PCT/GB03/01463 - 205 C 1 . 7 alkylene-C 5 - 2 0 arylene-C. 7 alkylene; or, and is optionally substituted; and has a backbone length of at least 4 atoms. 5
40. A compound according to any one of claims 1 to 25, wherein Q 2 , iS independently: Cs. 5 6 arylene-C. 7 alkylene; C 1 . 7 alkylene-Cs. 5 6 arylene; or, C 1 . 7 alkylene-Cs. 6 arylene-Clo 7 alkylene; and is optionally substituted; 10 and has a backbone length of at least 4 atoms.
41. A compound according to any one of claims 1 to 25, wherein Q 2 , is independently: phenylene-Cl 7 alkylene; Cl 7 alkylene-phenylene; or, 15 Cl 7 alkylene-phenylene-C- 7 alkylene; and is optionally substituted; and has a backbone length of at least 4 atoms.
42. A compound according to any one of claims 1 to 25, wherein Q 2 , is independently: 20 methylene-phenylene; ethylene-phenylene; phenylene-methylene; phenylene-ethylene; phenylene-ethenylene; 25 methylene-phenylene-methylene; methylene-phenylene-ethylene; methylene-phenylene-ethenylene; ethylene-phenylene-methylene; ethylene-phenylene-ethylene; 30 ethylene-phenylene-ethenylene; and is optionally substituted; and has a backbone length of at least 4 atoms. 35 WO 03/082288 PCT/GB03/01463 - 206
43. A compound according to claim 41 or 42, wherein the phenylene linkage is meta or para.
44. A compound according to claim 41 or 42, wherein the phenylene linkage is meta. 5
45. A compound according to claim 41 or 42, wherein the phenylene linkage is para. 10
46. A compound according to any one of claims 1 to 25, wherein Q 2 , is independently: morp morp
47. A compound according to any one of claims 1 to 25, wherein Q 2 , is independently: m or p 15
48. A compound according to any one of claims 1 to 26 and 37 to 41, wherein Q 2 is substituted. 20
49. A compound according to claim 48, wherein substituents on Q2 are independently: (1) ester; (2) amido; (3) acyl; 25 (4) halo; (5) hydroxy; (6) ether; (7) C 1 . 7 alkyl, including substituted C 1 -7alkyl; (8) C 5 - 2 0 aryl, including substituted C5- 2 0 aryl; 30 (9) sulfonyl; (10) sulfonamido; (11) amino; WO 03/082288 PCT/GB03/01463 - 207 (12) morpholino; (13) nitro; (14) cyano. 5
50. A compound according to claim 48, wherein substituents on Q2 are independently: (1) -C(=O)OMe, -C(=0)OEt, -C(=O)O(Pr), -C(=O)O(iPr), -C(=O)O(nBu), -C(=O)O(sBu), -C(=O)O(iBu), -C(=O)O(tBu), -C(=O)O(nPe); -C(=O)OCH 2 CH 2 OH, -C(=O)OCH 2 CH 2 OMe, -C(=O)OCH 2 CH 2 OEt; (2) -(C=O)NH 2 , -(C=O)NMe 2 , -(C=O)NEt 2 , -(C=O)N(iPr) 2 , -(C=O)N(CH 2 CH 2 OH) 2 ; 10 (3) -(C=O)Me, -(C=O)Et, -(C=O)-cHex, -(C=O)Ph; (4) -F, -CI, -Br, -I; (5) -OH; (6) -OMe, -OEt, -O(iPr), -O(tBu), -OPh; -OCFa, -OCH 2 CF 3 ; 15 -OCH 2 CH 2 OH, -OCH 2 CH 2 OMe, -OCH 2 CH 2 OEt; -OCH 2 CH 2 NH 2 , -OCH 2 CH 2 NMe 2 , -OCH 2 CH 2 N(iPr) 2 ; -OPh, -OPh-Me, -OPh-OH, -OPh-OMe, O-Ph-F, -OPh-CI, -OPh-Br, -OPh-1; (7) -Me, -Et, -nPr, -iPr, -nBu, -iBu, -sBu, -tBu, -nPe; -CFa, -CH 2 CF 3 ; 20 -CH 2 CH 2 OH, -CH 2 CH 2 OMe, -CH 2 CH 2 OEt; -CH 2 CH 2 NH 2 , -CH 2 CH 2 NMe 2 , -CH 2 CH 2 N(iPr) 2 ; -CH 2 -Ph; (8) -Ph, -Ph-Me, -Ph-OH, -Ph-OMe, -Ph-F, -Ph-CI, -Ph-Br, -Ph-I; (9) -SO 2 Me, -SO 2 Et, -SO 2 Ph; 25 (10) -SO 2 NH 2 , -SO 2 NMe 2 , -SO 2 NEt 2 ; (11) -NMe 2 , -NEt 2 ; (12) morpholino; (13) -NO 2 ; (14) -CN. 30
51. A compound according to any one of claims 1 to 47, wherein Q 2 is unsubstituted. 35
52. A compound according to any one of claims 1 to 51, wherein Q 2 has a backbone of at least 5 atoms. WO 03/082288 PCT/GB03/01463 - 208
53. A compound according to any one of claims 1 to 51, wherein Q 2 has a backbone of at least 6 atoms. 5**
54. A compound according to any one of claims 1 to 51, wherein Cy is independently C3- 20 carbocyclyl; and is optionally substituted. 10
55. A compound according to any one of claims 1 to 51, wherein Cy is independently C 3 - 20 carbocyclyl derived from one of the following: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopentene, cyclohexene, norbornane, adamantane, cyclopentanone, and cyclohexanone; and is optionally substituted. 15
56. A compound according to any one of claims 1 to 51, wherein Cy is independently C 3 - 20 heterocyclyl; and is optionally substituted.
57. A compound according to any one of claims 1 to 51, wherein Cy is independently C 3 - 20 heterocyclyl derived from one of the following: piperidine, azepine, 20 tetrahydropyran, morpholine, azetidine, piperazine, imidazoline, piperazinedione, and oxazolinone; and is optionally substituted.
58. A compound according to any one of claims 1 to 51, wherein Cy is independently C 5 - 20 aryl; and is optionally substituted. 25
59. A compound according to any one of claims 1 to 51, wherein Cy is independently Ce- 20 carboaryl or C5- 2 0 heteroaryl; and is optionally substituted.
60. A compound according to any one of claims 1 to 51, wherein Cy is independently 30 C5- 2 0 aryl derived from one of the following: benzene, pyridine, furan, indole, pyrrole, imidazole, pyrimidine, pyrazine, pyridizine, naphthalene, quinoline, indole, benzimidazole, benzothiofuran, fluorene, acridine, and carbazole; and is optionally substituted. WO 03/082288 PCT/GBO3/01463 - 209
61. A compound according to any one of claims 1 to 51, wherein Cy is independently an optionally substituted phenyl group.
62. A compound according to any one of claims 1 to 51, wherein Cy is optionally 5 substituted with one or more substituents as defined in claim 49.
63. A compound according to any one of claims 1 to 51, wherein Cy is optionally substituted with one or more substituents as defined in claim 50. 10
64. A compound according to claim 1, selected from the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof: 1 PX117402 28 PX118870 55 PX118911 2 PX117403 29 PX118871 56 PX118913 3 PX117404 30 PX118872 57 PX118914 4 PX117764 31 PX118873 58 PX118918 5 PX117768 32 PX118874 59 PX118927 6 PX118490 33 PX118875 60 PX118928 7 PX118491 34 PX118876 61 PX118929 8 PX118791 35 PX118877 62 PX118930 9 PX118792 36 PX118878 63 PX118931 10 PX118793 37 PX118882 64 PX118932 11 PX118794 38 PX118891 65 PX118933 12 PX118807 39 PX118892 66 PX118934 13 PX118810 40 PX118893 67 PX118935 14 PX118811 41 PX118894 68 PX118937 15 PX118812 42 PX118898 69 PX118951 16 PX118830 43 PX118899 70 PX118965 17 PX118831 44 PX118900 71 PX118967 18 PX118832 45 PX118901 72 PX118968 19 PX118844 46 PX118902 73 PX118969 20 PX118845 47 PX118903 74 PX118970 21 PX118846 48 PX118904 75 PX118971 22 PX118847 49 PX118905 76 PX118972 23 PX118848 50 PX118906 77 PX118978 24 PX118849 51 PX118907 78 PX118989 25 PX118850 52 PX118908 79 PX118990 26 PX118859 53 PX118909 80 PX118991 27 PX118860 54 PX118910 81 PX118994 WO 03/082288 PCT/GB03/01463 -210
65. A composition comprising a compound according to any one of claims 1 to 64 and 5 a pharmaceutically acceptable carrier.
66. A compound according to any one of claims 1 to 64 for use in a method of treatment of the human or animal body by therapy. 10
67. A compound according to any one of claims 1 to 64 for use in a method of treatment of a condition mediated by HDAC of the human or animal body by therapy.
68. A compound according to any one of claims 1 to 64 for use in a method of 15 treatment of a proliferative condition of the human or animal body by therapy.
69. A compound according to any one of claims 1 to 64 for use in a method of treatment of cancer of the human or animal body by therapy. 20
70. A compound according to any one of claims 1 to 64 for use in a method of treatment of psoriasis of the human or animal body by therapy.
71. Use of a compound according to any one of claims 1 to 64 for the manufacture of a medicament for use in the treatment of a condition mediated by HDAC. 25
72. Use of a compound according to any one of claims 1 to 64 for the manufacture of a medicament for use in the treatment of a proliferative condition.
73. Use of a compound according to any one of claims 1 to 64 for the manufacture of 30 a medicament for use in the treatment of cancer.
74. Use of a compound according to any one of claims 1 to 64 for the manufacture of a medicament for use in the treatment of psoriasis. 35
75. A method inhibiting HDAC in a cell comprising said cell with an effective amount of a compound according to any one of claims 1 to 64. WO 03/082288 PCT/GB03/01463 - 211
76. A method for the treatment of a condition mediated by HDAC comprising administering to a subject suffering from a condition mediated by HDAC a therapeutically-effective amount of a compound according to any one of claims 1 to 64. 5
77. A method for the treatment of a proliferative condition comprising administering to a subject suffering from a proliferative condition a therapeutically-effective amount of a compound according to any one of claims 1 to 64. 10
78. A method for the treatment of cancer comprising administering to a subject suffering from cancer a therapeutically-effective amount of a compound according to any one of claims 1 to 64.
79. A method for the treatment of psoriasis comprising administering to a subject 15 suffering from psoriasis a therapeutically-effective amount of a compound according to any one of claims 1 to 64.
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NZ536116A (en) 2007-01-26
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AU2003229883B2 (en) 2009-06-11
WO2003082288A1 (en) 2003-10-09
US7629343B2 (en) 2009-12-08
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